Canna~Fangled Abstracts

Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury.

By March 15, 2013 No Comments
2013 Mar 15;8(8):731-44. doi: 10.3969/j.issn.1673-5374.2013.08.008.

pub med big

Logo of nrr

Neural Regen Res. Mar 15, 2013; 8(8): 731–744. 
PMCID: PMC4146074

Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury

Abstract

One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.

Keywords: neural regeneration, reviews, perinatal hypoxia-ischemia, brain injury, brain plasticity, neuroprotective strategies, cannabinoid system, grants-supported paper, photographs-containing paper, neuroregeneration

Research Highlights

(1) A perinatal hypoxic-ischemic event is one of the most important causes of brain injury in the neonatal period.

(2) Hypoxia/ischemia leads to brain cell damage, finally resulting in brain cell death.

(3) The complex molecular mechanisms underlying hypoxic-ischemic brain injury cause unsatisfactory efficacy of treatments for this condition.

(4) A thorough understanding of the mechanisms underlying hypoxic-ischemic brain injury will provide new insights for the development of novel neuroprotective agents for this condition.

(5) The endocannabinoid system, which is naturally neuroprotective, is likely to play an important role in the prevention and treatment of hypoxic-ischemic brain injury.

INTRODUCTION

pm1Despite important advances in obstetric and neonatal care over the last 10 years, perinatal hypoxic-ischemic events still lead to significant mortality and morbidity in neonates. These events are one of the most important causes of neonatal brain injury and also result in adverse developmental outcomes[1,2]. The severity of the event, which often results in a dyskinetic cerebral palsy, is associated with multiple handicaps and hence a need for aid from society. Since hypoxic-ischemic brain injury is often unpredictable, the primary approach is to develop post-insult therapies to ameliorate ongoing or secondary injury[3]. In this regard, recent studies have focused on current knowledge surrounding neuroprotective therapies targeted towards the complexities of perinatal hypoxic-ischemic brain injury.

This article provides a comprehensive summary of the biochemical mechanisms underlying a perinatal hypoxic-ischemic event and a description of the morphological and molecular aspects of hypoxic-ischemic brain injury in neonates during intrauterine asphyxia.

Neuroprotective research has focused on pre-clinical studies of therapies that might reduce hypoxic-ischemic lesions to increase the opportunities of neonatal survival. Among them, cannabinoid compounds appear as a new therapeutic strategy with pharmacological properties for treatment of hypoxic-ischemic brain injury.

HYPOXIC-ISCHEMIC BRAIN INJURY

Hypoxic-ischemic encephalopathy, which is one of the most important causes of disabilities in term-born infants, leads to devastating long-term effects in the development of children[4]. The incidence of perinatal asphyxia ranges between 0.5–1% of all live births[5] and significant neurologic damage occurs in as many as 50–75% of these children[6]. Deficits include a variety of sensorimotor and cognitive impairments, depending on the extent, nature and location of the injury, as well as gestational age. These problems are encountered throughout development with a tremendous impact on the child, family, and society[7,8]. Despite the improvements in perinatal care, developmental neurological disorders are still a noteworthy problem[9].

It is necessary to take into account that the preterm neonate brain is more susceptible to hypoxic-ischemic events than the adult brain. Its cerebral vasculature makes the preterm neonate particularly vulnerable to periventricular and intraventricular hemorrhage. The preterm brain has more blood vessels, higher water content, lower myelin, a poorly developed cortex and a prominent germinal matrix[8]. Moreover, because of the vulnerability of immature oligodendrocytes in the white matter and the disruption in the myelination of motor tracts, common disorders, such as spastic paresis of the lower extremities, dyskinetic cerebral palsy and visual impairments, develop in children suffering hypoxic-ischemic brain injury[10,11,12,13,14,15,16].

To improve care in perinatal asphyxia, it is necessary to focus on the period of time following the hypoxicischemic event where therapeutic strategies could be efficacious in reducing brain injury. This period is normally short and may vary from 2 to 6 hours. Therefore, rapid identification would facilitate the application of diverse rescue strategies. To reduce the neurological consequences derived from hypoxic-ischemic brain injury, some actions are required: (1) improved monitoring in the perinatal period; (2) rapid identification of affected neonates; (3) preconditioning therapy (a therapeutic method that reduces the brain vulnerability) before hypoxic-ischemic encephalopathy; and (4) prompt institution of post-insult therapies to ameliorate the evolving injury[17,18].

BIOCHEMICAL AND PHYSIOLOGICAL EVENTS FOLLOWING HYPOXIC-ISCHEMIC BRAIN INJURY

The principal pathogenetic mechanism underlying neurological damage resulting from hypoxia-ischemia comprises a biphasic pattern of damage. An initial phase of early energetic failure is then followed by late energetic failure and occurs during reperfusion and reoxygenation several hours after the initial insult, and can last for days. The main cause of hypoxic-ischemic brain injury is the deprivation of glucose and oxygen, which results in a primary energy failure (first phase) and initiates a cascade of biochemical events leading to cell dysfunction and ultimately cell death[19,20,21,22].

During early energetic failure, the decrease in oxidative energy metabolism generates significant impairment in the extracellular balance of glutamate. Glutamate accumulation at synapses activates N-methyl-D- aspartate receptors. The uncontrolled stimulation of these receptors can lead to neuronal death through a process called excitotoxicity[21,23]. The subsequent release of excitatory amino acid transmitters and the formation of toxic free-radicals trigger a metabolic cascade on a slower time scale, leading to an influx of Ca2+ into neurons and promoting necrotic cell death. In this sense, necrosis is generated by organelle and cell swelling (cerebral edema), followed by the rupture of the plasma membrane and finally the dissolution of cell membranes in a zone surrounding the irreversibly damaged infarct core[23,24,25,26].

The secondary energy failure (second phase) varies according to the nature of the insult. High-energy phosphate levels recover from baseline levels[8,27,28] after reperfusion and a second decline in high-energy phosphate levels is pronounced in the next 48 hours[29,30,31]. This secondary phase is characterized by excessive entry of Ca2+ into cells, causing induction of free radicals, such as reactive oxygen species. Excitotoxic amino acids are also released and inflammatory reactions occur in the immediate zone surrounding the infarct i.e., the penumbra. These reactions promote cell death, mainly by apoptotic mechanisms including shrinkage[32,33,34,35,36], nuclear pyknosis (the nucleus loses density), chromatin condensation, and genomic fragmentation[37] (Figure 1).

Figure 1

Schematic distribution of brain injured regions with different severity of hypoxia-ischemia (HI).

This penumbral zone is characterized by a longer tolerance to ischemic stress and a slower rate of disintegration, due to a moderate metabolic derangement and minor abnormalities in cerebral blood flow[24,26]. This biphasic pattern produced during the hypoxic-ischemic event (Figure 2) creates a “therapeutic window”, a period in which the damaged but viable cells could be rescued by neuroprotective strategies. This window attracts much interest as a target for therapeutic strategies to reduce the damage derived from hypoxic-ischemic insults.

Figure 2

Cascade of biochemical reactions following hypoxic-ischemic (HI) brain injury[178].

IMMATURE BRAIN PLASTICITY AFTER HYPOXIC-ISCHEMIC BRAIN INJURY

Loss of cerebral function after hypoxic-ischemic brain injury is not only due to neuronal death in the infarcted tissue but also cell dysfunction in the penumbra. Therefore, it is important to take into account these surrounding penumbral areas that could survive the insult, as well as the non-ischemic ipsilateral tissue and the contralateral brain areas, which are connected to the area of damage[38,39,40].

Following hypoxic-ischemic brain injury, the neonatal nervous system is capable of making compensatory reorganization. This recovery depends on the severity, intensity and timing of injury[21,41,42]. This spontaneous reorganization occurs during a period proximate to injury and probably reflects the recovery of neurotransmission in tissue near to and distant from the injury location[43,44,45]. Therefore, affected neurons that are damaged by catabolic processes could be rapidly repaired by the neonatal nervous system[46]. However, these neurons might still exhibit aberrant neurotransmission, due to the presence of dysfunctional spines[47,48].

Immature brain has demonstrated a particularly strong capacity to recover from hypoxic-ischemic brain injury by producing neurogenesis in non-neurogenic vulnerable regions to ischemic injury, and in this way new neurons produced in the subventricular zone can migrate to injured areas in the neocortex[49,50]. This neocortical neuron migration, which has great importance for the remyelination of injured areas, also guarantees the survival of the new neurons[49], and coincides with the proliferation and migration of glial cells[51]. Furthermore, survival, repair and plasticity genes are rapidly reactivated after ischemia in response to damage, and growth-promoting factors are released to stimulate anabolic processes[52,53]. These remarkable observations suggest the brain has the potential to repair itself, which is relevant to therapies for various pathological conditions, such as ischemic brain injury.

Furthermore, delayed regeneration is possible because neural stem cells can renew and differentiate themselves into cells of all glial and neuronal lineages and can populate developing or degenerating central nervous system regions. Recent evidence suggests that hypoxic-ischemic brain injury can also be treated with mesenchymal stem cells[54], which are easily recovered from bone marrow, placental tissue, umbilical cord stroma and cord blood without ethical issues. Mesenchymal stem cells may also secrete several trophic factors including stimulating factor-1, vascular endothelial growth factor, basic fibroblast growth factor, nerve growth factor and brain-derived neurotrophic factor[55]. Intracranial administration of mesenchymal stem cells for 3–10 days after hypoxic-ischemic insult has shown decreased histological damage and improved outcome in rat models of hypoxic-ischemic brain injury[56].

THERAPEUTIC STRATEGIES FOR HYPOXIC-ISCHEMIC DAMAGE

Reducing neuronal death after oxygen deprivation has provided promising results in experimental therapy, especially in the developing nervous system[57,58]. The main strategies related to amelioration of injury after hypoxia-ischemia are those applied after the insult or reperfusion[1859]. In this sense, non-pharmacological therapies, such as hypothermia, which consist of minimizing cerebral metabolism[60], have high relevance in clinical practice. However, many studies are now focusing on the use of pharmacological therapies to treat specific aspects of hypoxic-ischemic brain injury.

Non-pharmacological therapies

Hypercapnea and hypothermia stand out amongst the non-pharmacological therapies for the treatment of brain injury. In experimental assays in rats, hypercapnea has been reported to reduce lung injury, increase cerebral blood flow, and protect the immature brain from hypoxic-ischemic brain injury[61]. Currently, hypothermia appears to be the most reliable intervention available for reducing the risk of death or disability in infants with brain injury[62,63]. A moderate temperature reduction (32–34°C) has now become a standard of care for neonatal hypoxic-ischemic brain injury[64,65].

Results from MRI studies regarding hypothermia therapy suggest that head and total body cooling is associated with a decrease in the incidence of basal ganglia/thalamic brain lesions[16]. Mechanisms based on hypothermic neuroprotection are an increase in neuronal survival in the basal ganglia and suppression of caspase-3 activation[66]. Hypothermia has also been shown to suppress microglial activation[67]. Furthermore, inflammation and expression levels of tumor necrosis factor-α, interleukin-1β and interleukin-18 are reduced[68] in this context, whereas an increase in the expression of the anti-inflammatory cytokine interleukin-10 has been observed[67,69].

Pharmacological therapies

Recent studies have demonstrated that the administration of a variety of pharmacological agents after perinatal asphyxia is effective in alleviating injury. These specific drugs are used to reduce toxic free radicals, inhibit the excessive influx of calcium into neurons, and minimize cerebral edema caused by hypoxia-ischemia[7,58,70].

Regarding free radical formation after a hypoxic-ischemic event, allopurinol, a xanthine oxidase inhibitor, reduced the formation of free radicals that cause tissue damage and helped to maintain the blood-brain barrier. Its effectiveness has been noted in several animal studies[71,72]. Another alternative is the use of antioxidants such as erythropoietin, which has antiapoptotic and angiogenic properties[73] and provides neuroprotection and neurogenesis in neonatal rats[74,75,76]. By contrast, melatonin reduces brain damage and inhibits the development of long-term effects from ischemic injury[76], while vitamin E is thought to be an antioxidant and free radical scavenger, thereby reducing the risk and severity of hypoxic-ischemic brain injury[77].

Furthermore, administration of MgSO4 has been suggested to act as a neuroprotective agent because magnesium ions block the N-methyl-D-aspartic acid receptors and can therefore act as potent antagonists of glutamate neurotoxicity[78]. Previous reports suggested that MgSO4 administration prevented the effects of energy depletion after a hypoxic-ischemic event in newborn children[79], and altered important enzymes in erythrocyte membranes from asphyxiated newborns, reducing post-asphyxial damage[80]. Likewise, other authors explain how MgSO4 has potential therapeutic benefits after the hypoxic-ischemic event, reducing the number of apoptotic cells[81].

Recently, several studies have indicated that cannabinoids have high potential as neuroprotective compounds, both in acute neurodegenerative diseases, such as hypoxic-ischemic or traumatic brain damage, and in chronic processes such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease[82,83,84]. These substances have emerged as neuroprotectants because they can modulate neuronal and glial responses. Additionally, cannabinoids have endothelial cell function, anti-excitotoxic[85,86], anti-inflammatory[86,87,88], and vasodilatory effects[89] and can also regulate calcium homeostasis[90,91,92]. New findings indicate that some anti-inflammatory treatments may actually improve recovery by promoting neurogenesis[92,93]. Cannabinoid receptor activation, therefore, is an important neuroprotective strategy for neonatal hypoxic-ischemic brain injury given its anti-inflammatory effect, with the synthetic cannabinoid WIN 55212 enhancing subventricular zone cell proliferation after neonatal hypoxic-ischemic brain injury[94].

NEUROPROTECTIVE EFFECTS OF THE CANNABINOID SYSTEM ON HYPOXIC-ISCHEMIC BRAIN INJURY

Up to now, different kinds of cannabinoid compounds have been described including phytocannabinoids, synthetic cannabinoids and those synthesized in the brain and certain peripheral tissues, named endogenous cannabinoids or endocannabinoids.

Phytocannabinoids

Phytocannabinoids are substances that normally have a carbocyclic structure of 21 carbons and are formed generally by three rings of cyclohexene, tetrahydropyran and benzene. These kinds of cannabinoids are produced by the cannabis plant, with the most representative molecules being tetrahydrocannabinol, cannabinol and cannabidiol[95].

Synthetic cannabinoids

The development of synthetic cannabinoids based on the chemical structure of phytocannabinoids has produced a large number of analogs. These compounds aimed to block the effects of the endogenous ligands by antagonizing cannabinoid receptors. For example, SR141716 or rimonabant[96] and AM251 are cannabinoid receptor type 1 receptor-selective antagonists, and SR144528[97] and AM630 are cannabinoid receptor type 2 receptor-selective antagonists. Alternatively, compounds can be designed to potentiate the effects associated with endogenous receptors through the use of specific agonists such as arachidonyl-2’- chloroethylamide (a cannabinoid receptor type 1 receptor-selective agonist), AM1241, JWH015 (a cannabinoid receptor type 2 receptor-selective agonists) or using non-selective agonists like CP55, 940[98], HU210 or WIN55, 212-2[99].

Endocannabinoids

Endocannabinoids are compounds produced within the body that have a lipid nature and are derived from polyunsaturated fatty acids with long chains. These compounds activate cannabinoid receptors and are synthesized in moments of intense activity of the brain[100]. The two most widely studied endocannabinoids are N-arachidonylethanolamide (anandamide)[101] and 2-arachidonoylglycerol[102,103]. Endocannabinoid names consist of the exogenous and endogenous ligands, the target receptors and the enzymes responsible for ligand biosynthesis, transport and degradation, such as N-acyltransferase, phospholipases, diacylglycerol lipase and the fatty acid amide hydrolase[104,105,106].

Endocannabinoid receptors

Endocannabinoids constitute a novel family of lipid ligands that act via specific G-protein-coupled receptors, cannabinoid receptor type 1 and cannabinoid receptor type 2[104]. Endocannabinoids can also interact with other receptors such as vanilloid receptors type 1[107], peroxisome proliferator-activated receptors and even the TWIK-related acid-sensitive potassium channel 1[108]. Moreover, some studies have also reported the interaction of anandamide with both muscarinic[109] and serotonergic receptors[110]. Cannabinoid receptor type 1 is widely expressed in neurons, with particularly high levels in the I and IV layers of the cerebral cortex, hippocampus, basal ganglia, cerebellum, and brainstem[104]. It can also be found in glial cells[95,108,111]. Such a distribution of cannabinoid receptor type 1 receptors suggests that cannabinoid agonists are involved in neuronal circuits related to coordination and modulation of movement, superior cognitive functions such as memory and reward mechanisms, response to stress and pain, regulation of sleep, body temperature, appetite, nausea and vomiting[107,109,110]. The activation of presynaptic cannabinoid receptor type 1 has its main neuroprotective capacity in the inhibition of glutamatergic neurotransmission[111,112,113,114], and avoiding massive accumulation of intracellular calcium, nitrogen and reactive oxygen species, which would trigger cell death[115].

Cannabinoid receptor type 2 is expressed mainly in cells of lymphoid origin, such as B and T lymphocytes, natural killer cells, mastocytes, macrophages and monocytes. Therefore, they may be involved in the immunomodulatory effect of cannabinoids[95,115,116]. Some reports have described the presence of cannabinoid receptor type 2 in brain cells, including neurons from the brain stem[105,116,117]. Cannabinoid receptor type 2 mediates the cannabinoid antiinflammatory and immunomodulatory effects[118,119], with a number of investigations showing that their activation has anti-inflammatory therapeutic potential in central nervous system diseases, such as multiple sclerosis, traumatic brain injury and Alzheimer’s disease[120,121]. Recently, it has been shown that the cannabinoid receptor type 2 is also found in resident inflammatory cells within the brain, such as microglia[122,123], and that hypoxia-ischemia induces its expression in the brain[119]. Thus, the use of cannabinoid receptor type 2 agonists has proven to be beneficial in different paradigms of neonatal hypoxic-ischemic brain injury[124,125,126], by reducing cell death accompanied by modulation of glutamate release, and decreasing production of cytokines, cyclooxygenase-2 and inducible nitric oxide synthase expression. These observations support the hypothesis that the protective effect of cannabinoid receptor type 2 relies mostly upon its anti-inflammatory effects and opens a new possibility for its use as a neuroprotective target following perinatal asphyxia.

Endogenous ligands

As mentioned above, the best characterized endogenous ligands are N-arachidonoylethanolamide and 2-arachidonoylglycerol[101,126,127,128]. N-arachidonoylethanolamide or anandamide has been found both in the brain and in the periphery[129]. Anandamide is an agonist for cannabinoid receptor type 1[130,131], cannabinoid receptor type 2[129,131], and the vanilloid receptor type 1 receptor[132]. In the brain, anandamide levels are high in the hippocampus, thalamus, striatum and brainstem, and lower, but still detectable, in the cerebral cortex and cerebellum[129,133]. Like anandamide, 2-arachidonoylglycerol is found both in the brain and in the periphery, although the concentrations found are approximately 150 times higher than those for anandamide[133]. 2-arachidonoylglycerol is found at high levels in the brainstem, hippocampus, striatum and medulla in rats, showing a correlation with anandamide but not cannabinoid receptor type 1 localization[133]. 2-arachidonoylglycerol is an agonist at cannabinoid receptor type 1 and also cannabinoid receptor type 2, having a greater potency than anandamide. This suggests that 2-arachidonoylglycerol may be the endogenous ligand for cannabinoid receptor type 2, and this finding could be due to the greater stability of 2-arachidonoylglycerol compared with anandamide[103,134].

In addition, unknown or poorly investigated endocannabinoids do exist. They are present in the mammalian nervous system but their exact physiological and pathological functional relevance is still obscure. In vitro assays demonstrated that some of these novel endocannabinoids act upon known cannabinoid receptors[135].

Endocannabinoid synthesis

The synthesis of endocannabinoids (Figure 3) results from an intense or prolonged release of excitatory neurotransmitters[136]. In response to postsynaptic depolarization, voltage-dependent calcium channels are opened, inducing an increase in intracellular calcium levels. This increase in intracellular Ca2+ stimulates the process of exocytosis. Neurotransmitter is released and then binds to the corresponding postsynaptic receptor, inducing the opening of Ca2+ channels; consequently, the postsynaptic neuron is depolarized. The increase of intracellular Ca2+ activates enzymes such as N-acyl-transferase, phospholipases A, C and D or diacylglycerol lipase. These enzymes synthesize endocannabinoids from membrane lipids including phosphatidylethanolamine or phosphatidylcholine. Once synthesized, the endocannabinoids leave the postsynaptic cells and activate cannabinoid receptor type 1 on presynaptic neurons. Through the activation of G proteins, Ca2+ presynaptic channels are inhibited, and neurotransmitter release is suppressed[137,138].

Figure 3

Role of cannabinoids in the modulation of synaptic transmission[169].

Anandamide is produced on demand from the hydrolysis of a pre-formed membrane phospholipid precursor N-arachidonoyl phosphatidylethanolamine by the action of N-arachidonoyl phosphatidylethanolamine- phospholipase-D[139,140]. In most tissues, anandamide removal is catalyzed by fatty acid amide hydrolase[141], but can also act as a substrate for palmitoylethanolamide- preferring acid amidase[142,143], cyclooxygenase-2, lipoxygenases, and cytochrome P450 to produce biologically active products. 2-arachidonoylglycerol is also synthesized on demand through the conversion of 2-arachidonate-containing phosphoinositides to diacylglycerols, which are then converted to 2-arachidonoylglycerol by the action of diacylglycerol lipase. Monoacyl glycerol lipase is the enzyme mainly responsible for its metabolism in vivo, although it can be also be metabolized by fatty acid amide as well as by cyclooxygenase-2 and lipoxygenases[140,141,142,143].

Neuroprotective effects

The neuroprotective effect provided by cannabinoid receptor activation occurs because of the modulation of synaptic transmission[144,145], plasticity, calcium homeostasis[95,103] and activation of cytoprotective signaling pathways[103].

It has been shown that endocannabinoids synthesized by depolarized postsynaptic dendrites, particularly 2-arachidonoylglycerol[146], can act as retrograde ligands at cannabinoid receptor type 1 located at presynaptic terminals to inhibit the release of excitatory or inhibitory neurotransmitters from the presynaptic neuron[147,148]. Moreover, endocannabinoids also play a key role in peripheral and brain immune function, including inhibiting the release of inflammatory mediators, such as nitric oxide, interleukin-2 and tumor necrosis factor-α. Endocannabinoids also inhibit the activation of cell-mediated immune processes, proliferation and chemotaxis[149,150].

Activation of cannabinoid receptors induces the closure of Ca2+ channels, thus inducing neuroprotection through the reduction of glutamate release[151,152]. Drugs reducing glutamate release are of particular value in neuroprotection in a neonatal hypoxic-ischemic event, as glutamate receptor blockers are neurotoxic in immature brains[4]. In addition, cannabinoids reduce direct N-methyl-D-aspartate toxicity by downstream inhibition of protein kinase A signaling and nitric oxide generation[153].

Several in vitro studies have reported neuroprotective effects of cannabinoids related to their antioxidant effect[154,155]. Also, in vivo models of neurodegenerative diseases have demonstrated antioxidant-related neuroprotective actions for cannabinoids[156]. It is known that cannabinoids reduce body temperature[157]. Studies in adult rats using different cannabinoids have demonstrated that hypothermia is a substantial part of the neuroprotective effect of these compounds, as warming reduces or even abolishes the beneficial effect[158,159]. Furthermore, cannabinoids cause vasodilation in the brain[160,161], stabilize the blood-brain barrier and are involved in neuroproliferative processes[162,163]. Cannabinoids enhance energy metabolism of astrocytes[144] and protect these glial cells against cytotoxic and proapoptotic stimuli[164].

Different studies postulate that administration of synthetic cannabinoids can reduce damage after brain injury[165,166,167,168,169,170]. Specifically, administration of WIN55212 just after recovery from hypoxia-ischemia successfully reduces brain injury as observed in a histopathological study by Fernandez-Lopez et al[167]. Moreover, WIN55212 reduces apoptotic cell death in all regions studied through the maintenance of mitochondrial integrity and functionality[171] and promotes neurogenesis in the subventricular zone, oligodendrogenesis, white matter remyelination, and neuroblast generation after neonatal hypoxic-ischemic events[172]. Additionally, the cannabinoid receptor type 1 antagonist AM281 and the diacylglycerol-lipase inhibitor O-3640 have been shown to exacerbate the detrimental effects of oxygen-glucose deprivation in an in vitro model by causing an excess in glutamate release. The cannabinoid receptor type 2 agonist, O-1966, has been found to increase blood flow to the brain and thus attenuate neuroinflammation in an animal model of stroke[173].

Administration of endogenous cannabinoids emerges as a novel neuroprotective therapy because of the observation that these substances take part in the natural mechanism for controlling damage. According to their neuroprotective effects, experimental in vitro studies confirmed that the endocannabinoids anandamide and 2-arachidonoylglycerol may attenuate injury in cortical cells in an oxygen-glucose deprivation model[173]. In an in vivo model of induced excitotoxicity, anandamide protects against neuronal injury[174]. Moreover, in a mouse model of closed head injury, administration of 2-arachidonoylglycerol significantly reduced brain edema, infarct volume and hippocampal cell death, and promoted clinical recovery[175]. Finally, administration of these two endocannabinoids after perinatal hypoxic-ischemic brain injury in a rat model remarkably ameliorated brain injury, reduced apoptotic cell death, maintained mitochondrial functionality and improved cellular parameters, including influx of calcium into cells and the production of reactive oxygen species[176]. These data support the hypothesis that the protective effects of endocannabinoids relies mostly upon their anti-apoptotic and anti-inflammatory effects, opening a new window for their possible use as neuroprotective agents following perinatal asphyxia.

SUMMARY

Cannabinoids emerge as effective neuroprotective compounds, given that the endogenous cannabinoid system is one of the natural mechanisms for controlling damage and induces the healing of diverse injuries. The antioxidant and immunomodulatory properties of cannabinoids, as well as their ability to reduce glutamate release and inducible nitric oxide synthase expression, make these compounds particularly attractive as neuroprotectants in neonatal hypoxic-ischemic encephalopathy given that glutamatergic excitotoxicity, toxic nitric oxide production, oxidative stress, and cytokine release are crucial elements of post-hypoxic- ischemic brain injury in newborns. Moreover, these compounds provide real and exciting prospects for clinical use in the future and give hope that better long-term outcomes may be possible for these patients.[178]

Acknowledgments

We are grateful to Prof. David Hallett Russell, from the Medical School of the University of the Basque Country, for his careful review of the manuscript.

Footnotes

Funding: This work was supported by grants from Funding Health Care of Spanish Ministry of Health, No. PS09/02326, and from the Basque Government, No. GCI-07/79, IT-287-07.

Conflicts of interest: None declared.

(Edited by Cao GD, Sharma S, Ray B/Song LP)

REFERENCES

[1] Glass HC, Ferriero DM. Treatment of hypoxic-ischemic encephalopathy in newborns. Curr Treat Options Neurol. 2007;9:414–423.  [PubMed]
[2] Gonzalez FF, Ferriero DM. Therapeutics for neonatal brain injury. Pharmacol Ther. 2008;120:43–53.[PubMed]
[3] Fan X, Kavelaars A, Heijnen CJ, et al. Pharmacological neuroprotection after perinatal hypoxic-ischemic brain injury. Curr Neuropharmacol. 2010;8:324–334. [PMC free article]  [PubMed]
[4] Hamrick SE, Ferriero DM. The injury response in the term newborn brain. can we neuroprotect? Curr Opin Neurol. 2003;16:147–154.  [PubMed]
[5] Gill MB, Perez-Polo Hypoxia ischemia-mediated cell death in neonatal rat brain. Neurochem Res. 2008;33:2379–2389.  [PubMed]
[6] Torfs CP, van den Berg B, Oechsli FW, et al. Prenatal and perinatal factors in the etiology of cerebral palsy. J Pediatr. 1990;116:615–619.  [PubMed]
[7] Carli G, Reiger I, Evans N. One-year neurodevelopmental outcome after moderate newborn hypoxic ischemic encephalopathy. J Paediatr Child Health. 2004;40:217–220.  [PubMed]
[8] du Plessis A, Volpe JJ. Perinatal brain injury in the preterm and term newborn. Curr Opin Neurol. 2002;15:151–157.  [PubMed]
[9] Berger R, Garnier Y. Perinatal brain injury. J Perinat Med. 2000;28:261–285.  [PubMed]
[10] Volpe JJ. Cerebral white matter injury of the premature infant: more common than you think. Pediatrics. 2003;11:176–180.  [PubMed]
[11] Maneru C, Junque C, Botet F, et al. Neuropsychological long- term sequelae of perinatal asphyxia. Brain Inj. 2001;12:1029–1039.  [PubMed]
[12] Yager JY, Armstrong EA, Black AM. Treatment of the term newborn with brain injury: simplicity as the mother of invention. Pediatr Neurol. 2009;40:237–243.  [PubMed]
[13] Himmelmann K, McManus V, Hagberg G, et al. Dyskinetic cerebral palsy in Europe: Trends in prevalence and severity. Arch Dis Child. 2009;94:921–926.  [PubMed]
[14] Dammann O, Hagberg H, Leviton A. Is periventricular leukomalacia an axonopathy as well as an oligopathy? Pediatr Res. 2001;49:453–457.  [PubMed]
[15] Leviton A, Gressens P. Neuronal damage accompanies perinatal white-matter damage. Trends Neurosci. 2007;30:473–478.  [PubMed]
[16] Logitharajah P, Rutherford MA, Cowan FM. Hypoxic-ischemic encephalopathy in preterm infants: Antecedent factors, brain imaging, and outcome. Pediatr Res. 2009;66:222–229.  [PubMed]
[17] Shalak LF, Laptook AR, Velaphi SC, et al. Amplitude- integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics. 2003;111:351–357.  [PubMed]
[18] Sanders RD, Manning HJ, Robertson NJ, et al. Preconditioning and postinsult therapies for perinatal hypoxic-ischemic injury at term. Anesthesiology. 2010;113:233–249.  [PubMed]
[19] Perlman JM. Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy. Pediatrics. 2006;117:S28–33.  [PubMed]
[20] Volpe JJ. Hypoxia-ischemic encephalopathy: Neuropathology and Pathogenesis. In: Volpe JJ, editor. Neurology of the Newborn. 5th ed. Philadelphia: Saunders Company; 2008. 
[21] Ferriero D. Neonatal brain injury. N Engl J Med. 2004;351:1985–1995.  [PubMed]
[22] Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev D R. 2001;7:56–64.  [PubMed]
[23] Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005;15:234–240.  [PubMed]
[24] Roberts TPL, Vexler Z, Derugin N, et al. High speed MRI of ischemic brain injury following stenosis of the middle cerebral artery. J Cereb Blood Flow Metab. 1993;13:940–946.  [PubMed]
[25] Martin B. Gill, Bockhorst K, Narayana P, et al. Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects. J Neurosci Res. 2008;86:3584–3604. [PMC free article]  [PubMed]
[26] Nedelcu J, Klein MA, Aguzzi A, et al. Biphasic edema after hypoxic-ischemic brain injury in neonatal rats reflects early neuronal and late glial damage. Pediatr Res. 1999;46:297–304.  [PubMed]
[27] Wyatt JS, Edwards AD, Azzopardi D, et al. Magnetic resonance and near infrared spectroscopy for investigation of perinatal hypoxic-ischaemic brain injury. Arch Dis Child. 1989;64:953–963.[PMC free article]  [PubMed]
[28] Yager JY, Brucklacher RM, Vannucci RC. Cerebral energy metabolism during hypoxia-ischemia and early recovery in immature rats. Am J Physiol. 1992;262:672–677.  [PubMed]
[29] Lorek A, Takei Y, Cady EB, et al. Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1994;36:699–706.  [PubMed]
[30] Penrice J, Lorek A, Cady EB, et al. Proton magnetic resonance spectroscopy of the brain during acute hypoxia- ischemia and delayed cerebral energy failure in the newborn piglet. Pediatr Res. 1997;41:795–802.  [PubMed]
[31] Vannucci RC, Towfighi J, Vannucci SJ. Secondary energy failure after cerebral hypoxia-ischemia in the immature rat. J Cereb Blood Flow Metab. 2004;24:1090–1097.  [PubMed]
[32] McRae A, Gilland E, Bona E, et al. Microglia activation after neonatal hypoxic-ischemia. Brain Res Dev Brain Res. 1995;84:245–252.  [PubMed]
[33] Bona E, Andersson AL, Blomgren K, et al. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res. 1999;45:500–509.  [PubMed]
[34] Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med. 2006;40:388–397.  [PubMed]
[35] Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol. 2011;69:743–758. [PMC free article]  [PubMed]
[36] Goñi de Cerio F, Alvarez A, Caballero A, et al. Early cell death in the brain of fetal preterm lambs after hypoxic-ischemic injury. Brain Res. 2007;1151:161–171.  [PubMed]
[37] Verklan MT. The chilling details: hypoxic-ischemic encephalopathy. J Perinat Neonatal Nurs. 2009;23:59–68.  [PubMed]
[38] Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol. 2006;16:258–264.  [PubMed]
[39] Witte OW, Bidmon HJ, Schiene K, et al. Functional differentiation of multiple perilesional zones after focal cerebral ischemia. J Cereb Blood Flow Metab. 2000;20:1149–1165.  [PubMed]
[40] Kim YR, Huang IJ, Lee SR, et al. Measurements of BOLD/CBV ratio show altered fMRI hemodynamics during stroke recovery in rats. J Cereb Blood Flow Metab. 2005;25:820–829.  [PubMed]
[41] Walton M, Connor B, Lawlor P, et al. Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res Rev. 1999;29:137–168.  [PubMed]
[42] Sugawara T, Fujimura M, Noshita N, et al. Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx. 2004;1(1):17–25. [PMC free article]  [PubMed]
[43] Carey LM, Seitz RJ. Functional neuroimaging in stroke recovery and neurorehabilitation: Conceptual issues and perspectives. Int J Stroke. 2001;2:245–264.  [PubMed]
[44] Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl J Med. 2001;352:1677–1684.[PMC free article]  [PubMed]
[45] Ruttan L, Martin K, Liu A, et al. Long-term cognitive outcome in moderate to severe traumatic brain injury: A meta-analysisexamining timed and untimed tests at 1 and 4.5 or more years after injury. Arch Phys Med Rehabil. 2001;89:69–76.  [PubMed]
[46] Katsman D, Zheng J, Spinelli K, et al. Tissue microenvironments within functional cortical subdivisions adjacent to focal stroke. J Cereb Blood Flow Metab. 2003;23:997–1009.  [PubMed]
[47] Zhang S, Boyd J, Delaney K, et al. Rapid reversible changes in dendritic spine structure in vivo gated by the degree of ischemia. J Neurosci. 2005;25:5333–5338.  [PubMed]
[48] Gisselsson LL, Matus A, Wieloch T. Actin redistribution underlies the sparing effect of mild hypothermia on dendritic spine morphology after in vitro ischemia. J Cereb Blood Flow Metab. 2005;25:1346–1355.  [PubMed]
[49] Ong J, Plane JM, Parent JM, et al. Hypoxic-ischemic injury stimulates subventricular zone proliferation and neurogenesis in the neonatal rat. Pediatr Res. 2005;58:600–606.  [PubMed]
[50] Yang Z, Covey MV, Bitel CL, et al. Sustained neocortical neurogenesis after neonatal hypoxic/ischemic injury. Ann Neurol. 2007;61:199–208.  [PubMed]
[51] Zaidi AU, Bessert DA, Ong JE, et al. New oligodendrocytes are generated after neonatal hypoxic-ischemic brain injury in rodents. Glia. 2004;46:380–390.  [PubMed]
[52] Rickhag M, Wieloch T, Gido G, et al. Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue. J Neurochem. 2006;96:14–29.  [PubMed]
[53] Kury P, Schroeter M, Jander S. Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non-ischemic cortex. Eur J Neurosci. 2004;19:1708–1720.[PubMed]
[54] Wei X, Du Z, Zhao L, et al. IFATS collection: The conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells. 2009;27:478–488.  [PubMed]
[55] Rivera FJ, Sierralta WD, Minguell JJ, et al. Adult hippocampus derived soluble factors induce a neuronal- like phenotype in mesenchymal stem cells. Neurosci Lett. 2006;406:49–54.  [PubMed]
[56] van Velthoven CT, Kavelaars A, van Bel F, et al. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010;24:387–393.  [PubMed]
[57] McLendon D, Check J, Carteaux P, et al. Implementation of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very low birth weight infants. Pediatrics. 2003;111:497–503.  [PubMed]
[58] Felderhoff-Mueser U, Buhrer C. Clinical measures to preserve cerebral integrity in preterm infants. Early Hum Dev. 2005;81:237–244.  [PubMed]
[59] Gunn AJ, Gunn T, de Haan H, et al. Dramatic neuronal rescue with prolonged selective head cooling after ischemiain fetal sheep. J Clin Invest. 1997;99:248–256. [PMC free article]  [PubMed]
[60] Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx. 2006;3:154–169. [PMC free article][PubMed]
[61] Vannucci R, Towfighi J, Bucklacher R, et al. Effect of extreme hypercapnia on hypoxic-ishcemic brain damage in the immature rat. Pediatr Res. 2001;49:799–803.  [PubMed]
[62] Compagnoni G, Pogliani L, Lista G, et al. Hypothermia reduces neurological damage in asphyxiated newborn infants. Biol Neonate. 2002;82:222–227.  [PubMed]
[63] Thoresen M, Whitelaw A. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant. Curr Opin Neurol. 2005;18:111–116.  [PubMed]
[64] Perlman JM, Wyllie J, Kattwinkel J, et al. Neonatal resuscitation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Pediatrics. 2010;126:1319–1344.  [PubMed]
[65] Sharnkaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012;366:2085–2092. [PMC free article]  [PubMed]
[66] Barrett RD, Bennet L, Davidson J, et al. Destruction and reconstruction: hypoxia and the developing brain. Birth Defects Res C Embryo Today. 2007;81:163–176.  [PubMed]
[67] Wagner CL, Eicher DJ, Katikaneni LD, et al. The use of hypothermia: A role in the treatment of neonatal asphyxia? Pediatr Neurol. 1999;21:429–443.  [PubMed]
[68] Silverstein FS, Barks JD, Hagan P, et al. Cytokines and perinatal brain injury. Neurochem Int. 1997;30:375–383.  [PubMed]
[69] Azzopardi D, Edwards AD. Hypothermia. Semin Fetal Neonatal Med. 2007;12:303–310.  [PubMed]
[70] Badr Zahr LK, Purdy I. Brain injury in the infant: the old, the new, and the uncertain. J Perinat Neonatal Nurs. 2006;20:163–175.  [PubMed]
[71] Van Bel F, Shadid M, Moison R, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998;10:185–193.  [PubMed]
[72] Legido A, Valencia I, Katsetos CD, et al. Neuroprotection in perinatal hypoxic-ischemic encephalopathy. Effective treatment and future perspectives. Medicina (B Aires) 2007;67:543–555.[PubMed]
[73] Sola A, Wen TC, Hamrick SE, et al. Potential for protection and repair following injury to the developing brain: a role for erythropoietin. Pediatr Res. 2005;57:110–117.  [PubMed]
[74] Chang YS, Mu D, Wendland M, et al. Eryhropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res. 2005;58:106–111.  [PubMed]
[75] Gonzalez FF, McQuillen P, Mu D, et al. Erythropoietin enhaces long term neuropretection and neurogenesis in neonatal strole. Dev Neurosci. 2007;29:321–330.  [PubMed]
[76] Signorini C, Ciccoli L, Leoncini S, et al. Free iron, total F-isoprostanes and total F-neuroprostanes in a model of neonatal hypoxic-ischemic encephalopathy: neuroprotective effect of melatonin. J Pineal Res. 2009;46:148–154.  [PubMed]
[77] Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2003;4:CD003665.  [PubMed]
[78] Solaroglu I, Kaptanoglu E, Okutan O, et al. Magnesium sulfate treatment decreases caspase-3 activity after experimental spinal cord injury in rats. Surg Neurol. 2005;64:17–21.  [PubMed]
[79] Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med. 2008;359:895–905. [PMC free article]  [PubMed]
[80] Szemraj J, Sobolewska B, Gulczynska E, et al. Magnesium sulfate effect on erythrocyte membranes of asphyxiated newborns. Clin Biochem. 2005;38:457–464.  [PubMed]
[81] Goñi-de-Cerio F, Alvarez A, Lara-Celador I, et al. Magnesium sulfate treatment decreases the initial brain damage alterations produced after perinatal asphyxia in fetal lambs. J Neurosci Res. 2012;90:1932–1940.  [PubMed]
[82] Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002;8:58–61.  [PubMed]
[83] Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006;105:1–25.  [PubMed]
[84] Maresz K, Pryce G, Ponomarev ED, et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB(1) on neurons and CB(2) on autoreactive T cells. Nat Med. 2007;13:492–497.[PubMed]
[85] Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001;15:300–302.  [PubMed]
[86] Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302:84–88.  [PubMed]
[87] Chang YH, Lee ST, Lin WW. Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J Cell Biochem. 2001;81:715–723.  [PubMed]
[88] Walter L, Franklin A, Witting A, et al. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci. 2003;23:1398–1405.  [PubMed]
[89] Parmentier-Batteur S, Jin K, Mao XO, et al. Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci. 2002;22:9771–9775.  [PubMed]
[90] Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83:1017–1066.  [PubMed]
[91] Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462. [PMC free article]  [PubMed]
[92] Barha CK, Ishrat T, Epp JR, et al. Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp Neurol. 2011;231:72–81. [PMC free article]  [PubMed]
[93] Whitney NP, Eidem TM, Peng H, et al. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem. 2009;108:1343–1359. [PMC free article]  [PubMed]
[94] Fernández-López D, Pradillo JM, García-Yébenes I, et al. The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia. Stroke. 2010;41:2956–2964.  [PubMed]
[95] Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202.  [PubMed]
[96] Rinaldi-Carmona M, Barth F, Héaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350:240–244.  [PubMed]
[97] Rinaldi-Carmona M, Barth F, Millan J, et al. SR144528, the first potent and selective agonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther. 1998;284:644–650.  [PubMed]
[98] Devane WA, Dysarz FA, Johnson Mr, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–613.  [PubMed]
[99] Bell MR, D’Ambra TE, Kumar V, et al. Antinociceptive (aminoalkyl)-indoles. J Med Chem. 1991;34:1099–1110.  [PubMed]
[100] Porter AC, Sauer JM, Knierman MD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther. 2002;301:1020–1024.[PubMed]
[101] Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–1949.  [PubMed]
[102] Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90.  [PubMed]
[103] Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid re- ceptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89–97.  [PubMed]
[104] Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–884.[PubMed]
[105] Di Marzo V, Bisogno T, De Petrocellis L. Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology. Chem Biol. 2007;14:741–756.  [PubMed]
[106] Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev. 2008;108:1687–1707. [PMC free article]  [PubMed]
[107] Pazos MR, Nunez E, Benito C, et al. Functional neuroanatomy of the endocannabinoid system. Pharmacol Biochem Behav. 2005;88:239–247.  [PubMed]
[108] Benito C, Romero JP, Tolon RM, et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007;27:2396–2402.  [PubMed]
[109] Lange JH, Kruse CG. Keynote review: Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists. Drug Discov Today. 2005;10(10):693–702.  [PubMed]
[110] Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(9):771–784.  [PubMed]
[111] Gerdeman G, Lovinger DM. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol. 2001;85:468–471.  [PubMed]
[112] Galante M, Diana MA. Group I metabotropic glutamate receptors inhibit GABA release atinterneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci. 2004;24:4865–4874.  [PubMed]
[113] Domenici MR, Azad SC, Marsicano G, et al. Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission. J Neurosci. 2006;26:5794–5799.  [PubMed]
[114] Nemeth B, Ledent C, Freund TF, et al. CB1 receptor-dependent and independent inhibition of excitatory postsynaptic currents in the hippocampus by WIN 55,212-2. Neuropharmacology. 2008;54:51–57. [PMC free article]  [PubMed]
[115] Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995;92:7162–7166. [PMC free article]  [PubMed]
[116] Guzman M, Sanchez C, Galve-Roperh I. Cannabinoids and cell fate. Pharmacol Ther. 2002;95:175–184.  [PubMed]
[117] Begg M, Pacher P, Batkai S, et al. Evidence for novel cannabinoid receptors. Pharmacol Ther. 2005;106:133–145.  [PubMed]
[118] Fernández-Ruiz J, Romero J, Velasco G, et al. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci. 2007;28:39–45.  [PubMed]
[119] Ashton JC, Rahman RMA. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett. 2007;412:114–117.  [PubMed]
[120] Mauler F, Horvath E, De Vry J, et al. BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. CNS Drug Rev. 2003;9:343–358.[PubMed]
[121] Ni X, Geller EB, Eppihimer MJ, et al. WIN55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model. Mult Scler. 2004;10:158–164.  [PubMed]
[122] Maresz K, Carrier EJ, Ponomarev ED, et al. Modulation of the cannabinoid CB receptor in microglial cells in response to inflammatory stimuli. J Neurochem. 2005;95(2):437–445.  [PubMed]
[123] Núñez E, Benito C, Pazos MR, et al. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53:208–213.  [PubMed]
[124] Fernandez-Lopez D, Martinez-Orgado J, Nuñez E, et al. Characterization of the neuroprotective effect of cannabinoid agonist WIN-55212 in an vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res. 2006;60:169–173.  [PubMed]
[125] Castillo A, Tolón MR, Fernández-Ruiz J, et al. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB2 and adenosine receptors. Neurobiol Dis. 2010;37:434–440.  [PubMed]
[126] Mechoulam R, Benshabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90.  [PubMed]
[127] Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature. 1997;388:773–778.  [PubMed]
[128] Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89–97.  [PubMed]
[129] Felder CC, Nielsen A, Briley EM, et al. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat. FEBS Lett. 1996;393:231–235.  [PubMed]
[130] Mackie K, Devane WA, Hille B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol. 1993;44:498–503.  [PubMed]
[131] Showalter VM, Compton DR, Martin BR, et al. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther. 1996;278:989–999.  [PubMed]
[132] Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–457.  [PubMed]
[133] Bisogno T, Berrendero F, Ambrosino G, et al. Brain regional distribution of endocannabinoids: implications for their biosynthesis and biologi- cal function. Biochem Biophys Res Commun. 1999;256:377–380.  [PubMed]
[134] Sugiura T, Kondo S, Kishimoto S, et al. Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem. 2000;275:605–612.  [PubMed]
[135] Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62:588–631. [PMC free article]  [PubMed]
[136] Kyrou I, Valsamakis G, Tsigos C. The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome. Ann N Y Acad Sci. 2006;1083:270–305.  [PubMed]
[137] Di Marzo V, Melck D, Bisogno T, et al. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998;21:521–528.  [PubMed]
[138] Maejima T, Hashimoto K, Yoshida T, et al. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron. 2001;31:463–475.  [PubMed]
[139] Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372:686–691.  [PubMed]
[140] Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol. 2004;61:149–160.  [PubMed]
[141] Ueda N. Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat. 2002;68-69:521–534.[PubMed]
[142] Ueda N, Yamanaka K, Yamamoto S. Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J Biol Chem. 2001;276:35552–35557.  [PubMed]
[143] Lo Verme J, Gaetani S, Fu J, et al. Regulation of food intake by oleoylethanolamide. Cell Mol Life Sci. 2005;62:708–716.  [PubMed]
[144] Stella N. Cannabinoid signaling in glial cells. Glia. 2004;48:267–277.  [PubMed]
[145] Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:678–682.[PubMed]
[146] Kim J, Alger BE. Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci. 2004;7:697–698.  [PubMed]
[147] Maejima T, Ohno-Shosaku T, Kano M. Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals. Neurosci Res. 2001;40:205–210.  [PubMed]
[148] Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature. 2001;410:588–592.  [PubMed]
[149] Coopman K, Smith LD, Wright KL, et al. Temporal variation in CB2R levels following T lymphocyte activation: evidence that cannabinoids modulate CXCL12-induced chemotaxis. Int Immunopharmacol. 2007;7:360–371.  [PubMed]
[150] Romero-Sandoval EA, Horvath R, Landry RP, et al. Cannabinoid receptor type 2 activation induces a microglial anti- inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol Pain. 2009;5:25. [PMC free article]  [PubMed]
[151] Hajos N, Ledent C, Freund TF. Novel cannabinoid- sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106:1–4.  [PubMed]
[152] Breivogel CS, Walker JM, Huang SM, et al. Cannabinoid signaling in rat cerebellar granule cells: G-protein activation, inhibition of glutamate release and endogenous cannabinoids. Neuropharmacology. 2004;47:81–91.  [PubMed]
[153] Kim SH, Won SJ, Mao XO, et al. Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity. Mol Pharmacol. 2006;69:691–696.  [PubMed]
[154] Hampson AJ, Grimaldi M, Axelrod J, et al. Cannabidiol and (-)Delta9- tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95:8268–8273. [PMC free article]  [PubMed]
[155] Marsicano G, Moosmann B, Hermann H, et al. Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem. 2002;80:448–456.  [PubMed]
[156] Lastres-Becker I, Molina-Holgado F, Ramos JA, et al. Cannabinoids provide neuroprotection in experimental models of Parkinsońs disease: involvement of their antioxidant properties and/or glial cell-mediated effects. Neurobiol Dis. 2005;19:96–107.  [PubMed]
[157] Pertwee RG, Nash K, Trayhurn P. Evidence that the hypothermic response of mice to delta-9- tetrahydrocannabinol is not mediated by changes in thermogenesis in brown adipose tissue. Can J Physiol Pharmacol. 1991;69:767–770.  [PubMed]
[158] Leker RR, Gai N, Mechoulam R, et al. Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke. 2003;34:2000–2006.  [PubMed]
[159] Ovadia H, Wohlman A, Mechoulam R, et al. Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens. Neuropharmacology. 1995;34:175–180.  [PubMed]
[160] Hillard CJ. Endocannabinoids and vascular function. J Pharmacol Exp Ther. 2000;294:27–32.[PubMed]
[161] Golech SA, McCarron RM, Chen Y, et al. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res. 2004;132:87–92.  [PubMed]
[162] Fernandez-Ruiz J, Berrendero F, Hernandez ML, et al. The endogenous cannabinoid system and brain development. Trends Neurosci. 2000;23:14–20.  [PubMed]
[163] Aguado T, Palazuelos J, Monory K, et al. The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J Neurosci. 2006;26:1551–1561.  [PubMed]
[164] Docagne F, Muñetón V, Clemente D, et al. Excitotoxicity in a chronic model of multiple sclerosis: neuroprotective effect of cannabinoids through CB1 and CB2 receptor activation. Mol Cell Neurosci. 2007;34:551–561.  [PubMed]
[165] Alonso-Alconada D, Alvarez FJ, Alvarez A, et al. The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic-ischemic injury in fetal lambs. Brain Res. 2010;1362:150–159.  [PubMed]
[166] Alvarez FJ, Lafuente H, Rey-Santano MC, et al. Neuroprotective effects of the non-psychoactive cannabinoid cannabidiol in hypoxic-ischemic newbornpiglets. Pediatr Res. 2008;64:653–658.  [PubMed]
[167] Fernandez-Lopez D, Pazos MR, Tolon RM, et al. The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats. Pediatr Res. 2007;62:255–260.  [PubMed]
[168] Martinez-Orgado J, Fernandez-Lopez D, Moro MA, et al. Nitric oxide synthase as a target for the prevention of hypoxic-ischemic newborn brain damage. Curr Enzyme Inhib. 2006;2:219–229.
[169] Martinez-Orgado J, Fernandez-Lopez D, Lizasoain I, et al. The seek of neuroprotection: introducing cannabinoids. Recent Pat CNS Drug Discovery. 2007;2:131–139.  [PubMed]
[170] Alonso-Alconada D, Alvarez A, Alvarez FJ, et al. The cannabinoid WIN 55212-2 mitigates apoptosis and mitochondrial dysfunction after hypoxia ischemia. Neurochem Res. 2012;37:161–170.[PubMed]
[171] Fernández-López D, Pradillo JM, García-Yébenes, et al. The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia. Stroke. 2010;41:2956–2964.  [PubMed]
[172] Zhang M, Martin BR, Adler MW, et al. Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke. J Neuroimmun Pharmacol. 2009;4:249–259.[PMC free article]  [PubMed]
[173] Sinor AD, Irvin SM, Greenberg DA. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett. 2000;278:157–160.  [PubMed]
[174] van der Stelt M, Veldhuis WB, van Haaften GW, et al. Exogenous anandamide protects rat brain against acute neuronal injury in vivoJ Neurosci. 2001;21:8765–8771.  [PubMed]
[175] Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 2001;413:527–531.  [PubMed]
[176] Lara-Celador I, Castro-Ortega L, Alvarez A, et al. Endocannabinoids reduce cerebral damage after hypoxic-ischemic injury in perinatal rats. Brain Res. 2012;1474:91–99.  [PubMed]
[177] Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7–35. [PMC free article]  [PubMed]
[178] Hilario E, Alvarez A, Alvarez FJ, et al. Cellular mechanisms in perinatal hypoxic-ischemic brain Injury. Curr Pediatr Rev. 2006;2:131–141.

Articles from Neural Regeneration Research are provided here courtesy of Medknow Publications

 

twin memes II
en English