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Vol. 54, Issue 3, 459-462, September 1998

Cannabinoid Receptor Agonists Protect Cultured Rat Hippocampal Neurons from Excitotoxicity

Maoxing Shen and Stanley A. Thayer

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

	Summary

Top Summary Introduction Materials & Methods Results Discussion References

Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimimetics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg²⁺ concentration to 0.1 mM evoked a repetitive pattern of intracellular Ca²⁺ concentration ([Ca²⁺]_i) spiking that, when maintained for 24 hr, resulted in significant neuronal death. The [Ca²⁺]_i spiking and cell death in this model result from excessive activation of N-methyl-D-aspartate receptors, as indicated by the inhibition of both [Ca²⁺]_i spiking and neuronal death by the N-methyl-D-aspartate receptor antagonist CGS19755 (10 µM). The cannabimimetic drug Win55212-2 (100 nM) completely blocked [Ca²⁺]_i spiking and prevented neuronal death induced by low extracellular Mg²⁺ concentrations. These effects on [Ca²⁺]_i spiking and viability were stereoselective and were prevented by the CB1 receptor antagonist SR141716 (100 nM). The partial agonist CP55940 (100 nM) also afforded significant protection from excitotoxicity. Cannabimimetic drugs did not protect cells from the direct application of glutamate (30 µM). These data suggest that cannabimimetic drugs may slow the progression of neurodegenerative diseases.

	Introduction

Top Summary Introduction Materials & Methods Results Discussion References

The medicinal use of marijuana is controversial (Annas, 1997). The euphoria produced by ⁹-tetrahydrocannabinol, the principal psychoactive ingredient in marijuana, has led to the widespread recreational use of this drug. Therefore, the potential for abuse must be weighed against the therapeutic benefits of cannabimimetics. These drugs have been reported to be effective in the treatment of chronic pain, glaucoma, epilepsy, and the wasting and emesis associated with acquired immunodeficiency syndrome and cancer chemotherapy (Plasse et al., 1991; Howlett, 1995; Abood and Martin, 1996; Adams and Martin, 1996). The in vitro studies described in this report suggest additional therapeutic applications for cannabimimetic drugs.

Cannabinoid receptors are distributed throughout the central nervous system (Herkenham et al., 1990) and are present at high densities on the presynaptic terminals of glutamatergic synapses (Twitchell et al., 1997). We previously reported that the activation of these receptors attenuates glutamatergic neurotransmission by acting presynaptically to inhibit the release of glutamate (Shen et al., 1996). Presumably, activated CB1 receptors, acting via inhibitory G proteins (Childers et al., 1993), activate K⁺ channels (Deadwyler et al., 1993; Henry and Chavkin, 1995; Mackie et al., 1995) and inhibit Ca²⁺ channels (Mackie and Hille, 1992; Twitchell et al., 1997; Shen and Thayer, 1998), resulting in reductions in the release of neurotransmitter. Drugs that attenuate glutamatergic synaptic transmission show promise for the treatment of neurodegenerative disorders (Meldrum, 1993; Choi, 1994; Rothman and Olney, 1995). Several drugs that protect cells from excitotoxic neuronal death have a presynaptic component to their actions, including those that activate adenosine receptors (Abele et al., 1990; Thompson et al., 1992), activate K⁺ channels (Abele and Miller, 1990), and inhibit voltage-gated Ca²⁺ channels (Yamada et al., 1994).

Here we evaluate several cannabimimetic agents for their abilities to inhibit an aberrant pattern of glutamatergic synaptic activity and the neurotoxicity that results from it. Cannabinoid receptor agonists, acting via CB1 receptors, act potently and stereoselectively to inhibit [Ca²⁺]_i spiking and neuronal death evoked by excitation of the synaptic network that forms in cultures of rat hippocampal neurons.

	Materials and Methods

Top Summary Introduction Materials & Methods Results Discussion References

Materials were obtained from the following companies: NMDA, Win55212-2, Win55212-3, and CP55940 (levorotatory enantiomer), RBI (Natick, MA); SR141716, Sanofi Recherche (Montpellier, France); all other reagents, Sigma Chemical Co. (St. Louis, MO). Rat hippocampal neurons were grown in primary culture as previously described (Shen et al., 1996). Neurons dissociated from hippocampi of embryonic day 17 rats were plated as droplets on microetched coverslips (Belco Biotechnology, Vineland, NJ), at a density of 5 × 10⁴ cells/well (approximately 2.2 × 10⁴ cells/cm²). Cultures were grown without mitotic inhibitors for a minimum of 12 days before use. For neurotoxicity experiments, at least 100 neurons were counted on each coverslip. Coverslips were then treated with the appropriate control or reduced-[Mg²⁺]_o solutions, and the same fields of cells were recounted 18-24 hr later. Drugs, when included, were added to the 0.1 mM Mg²⁺ medium before application to the cells. Viable neurons were identified based on morphological criteria; they were phase-bright, had rounded somata, and extended long fine processes. In some experiments, viability was confirmed by demonstrating that cells identified as viable also excluded propidium iodide (2 µg/ml). We found that pairing pretreatment and post-treatment cell counts provided more reproducible assessments of the relatively modest degree of cell death resulting from this treatment. Analysis of variance with Bonferoni's post hoc test was used to determine significance. Data are presented as mean ± standard error. [Ca²⁺]_i was measured in single hippocampal neurons using indo-1-based microfluorimetry, as described previously (Shen et al., 1996).

	Results

Top Summary Introduction Materials & Methods Results Discussion References

Reduction of [Mg²⁺]_o to 0.1 mM elicits an intense pattern of [Ca²⁺]_i spiking activity that depends on glutamatergic synaptic transmission (Shen et al., 1996). As shown in Fig. 1, the cannabinoid receptor agonist Win55212-2 was a potent inhibitor of this synaptic activity. The Win55212-2-induced inhibition of low-[Mg²⁺]_o-induced [Ca²⁺]_i spiking was mediated by the CB1 receptor, as indicated by the complete reversal of the effect by the CB1 receptor antagonist SR141716 (100 nM) (three experiments).

View larger version (60K): [in this window] [in a new window]   Fig. 1.   Cannabimimetics inhibit glutamatergic synaptic activity via CB1 receptors. Excitatory synaptic activity was induced by reducing [Mg2+]o to 0.1 mM, and the resulting [Ca2+]i spiking activity was recorded from a single hippocampal neuron using indo-1-based microfluorimetry. The [Mg2+]o was 0.1 mM throughout the recording, and 100 nM Win55212-2 and 100 nM SR141716 were applied by superfusion at the times indicated (horizontal bars).

The excitatory synaptic activity elicited by reduction of the [Mg²⁺]_o in central nervous system cultures has been shown to produce neurotoxicity, when sustained (Abele et al., 1990; Rose et al., 1990). The efficacy of cannabimimetics in reducing [Ca²⁺]_i spiking activity led us to hypothesize that cannabinoid receptor agonists would protect cells from this form of excitotoxicity. Cell viability was determined by counting the number of viable neurons before and 18-24 hr after treatment, as described in Materials and Methods. In control cultures (medium exchange only), 22 ± 2% of the neurons died (Fig. 2A). This value is in good agreement with the previous observation that, as central nervous system cultures mature in vitro, increased synaptic activity parallels spontaneous cell death (Peterson et al., 1989). Reducing [Mg²⁺]_o to 0.1 mM increased neuronal death to 42 ± 3% (19 experiments) (Fig. 2B), which was a significant increase relative to control cultures from the same plating (p < 0.001). These levels of spontaneous and low-[Mg²⁺]_o-induced cell death are in good agreement with findings from previous reports describing the use of this model of synaptically mediated cell death (Abele et al., 1990; Rose et al., 1990). As shown in Figs. 2C and 3, 100 nM Win55212-2 was a very effective neuroprotective agent. In the presence of Win55212-2, only 23 ± 3% of the neurons died; this value is comparable to that seen in the control wells (22 ± 2%) and is significantly less than that seen with 0.1 mM [Mg²⁺]_o (p < 0.001). The neuroprotection afforded by 100 nM Win55212-2 was blocked by 100 nM SR141716, consistent with a CB1-mediated process (Fig. 3A). The antagonist alone had no effect on cell viability. The inactive enantiomer Win55212-3 was also without effect. We previously showed that CP55940 acts as a partial agonist to inhibit low-[Mg²⁺]_o-induced [Ca²⁺]_i spiking activity in these hippocampal cultures (Shen et al., 1996). This compound was highly effective in preventing low-[Mg²⁺]_o-induced neurotoxicity, as shown in Fig. 3. Consistent with the glutamatergic mechanism of this excitotoxic model, the NMDA receptor antagonist CGS19755 (10 µM) not only prevented low-[Mg²⁺]_o-induced cell death but also improved viability, relative to the control cultures.

View larger version (205K): [in this window] [in a new window]   Fig. 2.   A cannabinoid receptor agonist protects cells against 0.1 mM [Mg2+]o-induced neurotoxicity. Phase-contrast photomicrographs show the same field of cultured rat hippocampal neurons before treatment (left) and 18-24 hr after treatment (right). Neurons (identified by a light halo around the soma and long fine processes) grew on a bed of non-neuronal cells that formed a mosaic beneath them. The neurons were treated with fresh medium (A), 0.1 mM [Mg2+]o (B), or 0.1 mM [Mg2+]o plus 100 nM Win55212-2 (C). Image contrast was enhanced digitally.

View larger version (29K): [in this window] [in a new window]   Fig. 3.   Cannabimimetics are neuroprotective. Excitotoxicity was elicited by treatment with 0.1 mM [Mg2+]o (Fig. 2) and was quantified as described in Materials and Methods. The limited size of each culture plating precluded the testing of all treatments on a single plating. Therefore, each treatment has separate bars for control () and for 0.1 mM [Mg2+]o-induced death (). In all experiments, 0.1 mM [Mg2+]o induced significantly greater cell death, relative to control wells. Drugs were applied at the following concentrations: Win55212-2, 100 nM; SR141716, 100 nM; Win55212-3, 100 nM; CP55940, 100 nM; CGS19755, 10 µM. A, Drugs were applied with 0.1 mM [Mg2+]o (), as indicated below the histogram. B, Cells were treated for 18-24 hr with 0.1 mM [Mg2+]o, 30 µM glutamate (Glu), and drug, as indicated (horizontal bars) above the histogram. The specific drugs added are indicated below the histogram. *, p < 0.05; **, p < 0.001, 0.1 mM [Mg2+]o versus control; +, p < 0.05; ++, p < 0.01; +++, p < 0.001, drug plus 0.1 mM [Mg2+]o versus 0.1 mM [Mg2+]o; #, p < 0.001, glutamate plus 0.1 mM [Mg2+]o plus CGS19755 versus glutamate plus 0.1 mM [Mg2+]o (analysis of variance with Bonferoni's post hoc test).

In a previous study, we found that CP55940 and Win55212-2 inhibited glutamatergic synaptic transmission, in identically prepared hippocampal cultures, by acting presynaptically to inhibit the release of glutamate (Shen et al., 1996). If the neuroprotection we describe here resulted from inhibition of glutamate release, then cannabimimetics would not be predicted to protect cells from the direct application of glutamate. This was indeed the case, as shown in Fig. 3B. Treatment of the cultures with 30 µM glutamate in medium with 0.1 mM [Mg²⁺]_o resulted in 62 ± 8% cell death after a 18-24-hr exposure. This toxicity was completely prevented by including the NMDA receptor antagonist CGS19755 (10 µM) in the medium. However, neither Win55212-2 (100 nM) nor CP55940 (100 nM) influenced the survival of the cultures. Thus, cannabimimetics protect cells from synaptically mediated excitotoxicity but not from exposure to exogenous glutamate.

	Discussion

Top Summary Introduction Materials & Methods Results Discussion References

In this report, we show that cannabinoid receptor agonists inhibit the [Ca²⁺]_i spiking and neurotoxicity induced in hippocampal cultures by the reduction of [Mg²⁺]_o to 0.1 mM. This action was stereoselective and mediated by the CB1 receptor. Excitotoxicity, such as that produced in this model system, is thought to underlie an number of neurodegenerative disorders, suggesting that cannabimimetics may prove useful in slowing neurodegenerative processes.

Cannabimimetic compounds with neuroprotective effects have been described previously, although this is the first description of neuroprotective effects mediated by the CB1 receptor. HU-211 was shown to protect neurons from NMDA-mediated neurotoxicity by acting as an antagonist at the NMDA receptor (Nadler et al., 1993). The endogenous lipid palmitoylethanolamide, acting on CB2 receptors via an unknown mechanism, protected cultured cerebellar granule cells from the direct application of NMDA (Skaper et al., 1996). In this report, we show that cannabinoids, acting through presynaptic CB1 receptors, protected cells from excitotoxicity. Cannabimimetics protected cells from the synaptic release of glutamate but not from the direct application of glutamate.

Excitotoxicity mediated by glutamate contributes to neuronal loss after acute insults, such as hypoxia-hypoglycemia, seizures, and head trauma (Meldrum, 1993; Choi, 1994; Rothman and Olney, 1995). A sensitization to glutamatergic input may also underlie more chronic neurodegenerative processes, such as Huntington's disease. Indeed, Beal et al. (1993) hypothesized that reduced block of the NMDA receptor by Mg²⁺ may underlie a number of neurodegenerative processes, suggesting that the in vitro model used here might identify drugs of use in these diseases. Furthermore, reductions in [Mg²⁺]_o have been widely used to evoke epileptic discharges from a variety of neuronal preparations (Kohr and Heinemann, 1989; Abele et al., 1990; Rose et al., 1990). Our observation that cannabimimetics inhibit paroxysmal neuronal firing is consistent with previous reports indicating that cannabimimetics have antiepileptic properties (Yoshida et al., 1995).

The neuroprotective efficacy of the compound CP55940 was of particular interest. This drug is a partial agonist that attenuates but does not block excitatory neurotransmission (Shen et al., 1996). Drugs that completely block glutamatergic synaptic transmission have serious psychotomimetic side effects (Olney, 1989). In contrast, drugs that are partial agonists may prove to have a greater margin of safety. Indeed, ⁹-tetrahydrocannabinol acts as a partial agonist to inhibit excitatory neurotransmission (Shen and Thayer, 1997), consistent with the safety (at least in terms of acute lethality) of drugs that attenuate but do not block glutamatergic synaptic transmission.

In conclusion, our data demonstrate that cannabinoid receptor agonists prevent excitotoxicity in vitro. We hypothesize that cannabimimetics would reduce the size of lesions in animal models of stroke, epilepsy, and metabolic disease, and we speculate that these drugs might be useful in treating neurodegenerative disorders.

	Acknowledgments

We gratefully acknowledge Sanofi Recherche for providing SR141716.

	Footnotes

Received March 5, 1998; Accepted May 27, 1998

This work was supported by grants from the National Institute on Drug Abuse (DA07304 and DA09293) and the National Science Foundation (IBN9723796). M.S. was supported by National Institute on Drug Abuse Training Grant DA07097.

Send reprint requests to: Dr. S. A. Thayer, Department of Pharmacology, University of Minnesota Medical School, 3-249 Millard Hall, 435 Delaware St. SE, Minneapolis, MN 55455. E-mail: thayer{at}med.umn.edu

	Abbreviations

[Ca²⁺]_i, intracellular Ca²⁺ concentration; [Mg²⁺]_o, extracellular Mg²⁺ concentration; NMDA, N-methyl-D-aspartate; CGS19755, (±)-2-amino-5-phosphonopentanoic acid; Win55212-2 (R-enantiomer), (+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone monomethanesulfonate ; Win55212-3, S-enantiomer of Win55212; SR141716, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide; CP55940, [1,2(R),5]-()-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol.

	References

Top Summary Introduction Materials & Methods Results Discussion References

• Abele A and Miller R (1990) Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons. Neurosci Lett  115: 195-200[Medline].
• Abele AE, Scholz KP, Scholz WK and Miller RJ (1990) Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons. Neuron  4: 413-419[Medline].
• Abood ME and Martin BR (1996) Molecular neurobiology of the cannabinoid receptor. Int Rev Neurobiol  39: 197-221[Medline].
• Adams IB and Martin BR (1996) Cannabis: pharmacology and toxicology in animals and humans. Addiction  91: 1585-1614[Medline].
• Annas GJ (1997) Reefer madness: the federal response to California's medical-marijuana law. N Engl J Med  337: 435-439[Free Full Text].
• Beal MF, Hyman BT and Koroshetz W (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci  16: 125-131[Medline].
• Childers SR, Pacheco MA, Bennett BA, Edwards TA, Hampson RE, Mu J and Deadwyler SA (1993) Cannabinoid receptors: G-protein-mediated signal transduction mechanisms. Biochem Soc Symp  59: 27-50[Medline].
• Choi DW (1994) Glutamate receptors and the induction of excitotoxic neuronal death. Prog Brain Res  100: 47-51[Medline].
• Deadwyler SA, Hampson RE, Bennett BA, Edwards TA, Mu J, Pacheco MA, Ward SJ and Childers SR (1993) Cannabinoids modulate potassium current in cultured hippocampal neurons. Recept Channels  1: 121-134[Medline].
• Henry DJ and Chavkin C (1995) Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. Neurosci Lett  186: 91-94[Medline].
• Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR and Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA  87: 1932-1936[Abstract/Free Full Text].
• Howlett A (1995) Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol  35: 607-634[Medline].
• Kohr G and Heinemann U (1989) Effects of NMDA antagonists on picrotoxin-, low Mg²⁺- and low Ca²⁺-induced epileptogenesis and on evoked changes in extracellular Na⁺ and Ca²⁺ concentrations in rat hippocampal slices. Epilepsy Res  4: 187-200[Medline].
• Mackie K and Hille B (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA  89: 3825-3829[Abstract/Free Full Text].
• Mackie K, Lai Y, Westenbroek R and Mitchell R (1995) Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci  15: 6552-6561[Abstract/Free Full Text].
• Meldrum BS (1993) Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol  3: 405-412[Medline].
• Nadler V, Mechoulam R and Sokolovsky M (1993) The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta-6-tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain. Neurosci Lett  162: 43-45[Medline].
• Olney JW (1989) Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry  26: 505-525[Medline].
• Peterson C, Neal JH and Cotman CW (1989) Development of N-methyl-D-aspartate excitotoxicity in cultured hippocampal neurons. Dev Brain Res  48: 187-195[Medline].
• Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV and Wadleigh RG (1991) Recent clinical experience with dronabinol. Pharmacol Biochem Behav  40: 695-700[Medline].
• Rose K, Christine C and Choi D (1990) Magnesium removal induces paroxysmal neuronal firing and NMDA receptor-mediated neuronal degeneration in cortical cultures. Neurosci Lett  115: 313-317[Medline].
• Rothman S and Olney J (1995) Excitotoxicity and the NMDA receptor: still lethal after eight years. Trends Neurosci  18: 57-58[Medline].
• Shen M, Piser TM, Seybold VS and Thayer SA (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci  16: 4322-4334[Abstract/Free Full Text].
• Shen M and Thayer SA (1997) ⁹-Tetrahydrocannabinol acts as a partial agonist to inhibit glutamatergic synaptic transmission between cultured rat hippocampal neurons. Soc Neurosci Abstr  23: 2312.
• Shen M and Thayer SA (1998) The cannabinoid agonist Win55212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain Res  783: 77-84[Medline].
• Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L and Leon A (1996) The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci USA  93: 3984-3989[Abstract/Free Full Text].
• Thompson SM, Haas HL and Gahwiler BH (1992) Comparison of the actions of adenosine at pre- and postsynaptic receptors in the rat hippocampus in vitro. J Physiol (Lond)  451: 347-363[Abstract/Free Full Text].
• Twitchell W, Brown S and Mackie K (1997) Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol  78: 43-50[Abstract/Free Full Text].
• Yamada K, Teraoka T, Morita S, Hasegawa T and Nabeshima T (1994) -Conotoxin GVIA protects against ischemia-induced neuronal death in the mongolian gerbil but not against quinolinic acid-induced neurotoxicity in the rat. Neuropharmacology  33: 251-254[Medline].
• Yoshida H, Usami N, Ohishi Y, Watanabe K, Yamamoto I and Yoshimura H (1995) Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives. Chem Pharm Bull (Tokyo)  43: 335-337[Medline].

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MOLECULAR PHARMACOLOGY, 54:459-462 (1998).
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics

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				F. Mauler, J. Mittendorf, E. Horvath, and J. de Vry Characterization of the Diarylether Sulfonylester (-)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a Potent Cannabinoid Receptor Agonist with Neuroprotective Properties J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 359 - 368. [Abstract] [Full Text] [PDF]

				A. C. Howlett, F. Barth, T. I. Bonner, G. Cabral, P. Casellas, W. A. Devane, C. C. Felder, M. Herkenham, K. Mackie, B. R. Martin, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors Pharmacol. Rev., June 1, 2002; 54(2): 161 - 202. [Abstract] [Full Text] [PDF]

				M. van der Stelt, W. B. Veldhuis, G. W. van Haaften, F. Fezza, T. Bisogno, P. R. Bar, G. A. Veldink, J. F. G. Vliegenthart, V. Di Marzo, and K. Nicolay Exogenous Anandamide Protects Rat Brain against Acute Neuronal Injury In Vivo J. Neurosci., November 15, 2001; 21(22): 8765 - 8771. [Abstract] [Full Text] [PDF]

				M. van der Stelt, W. B. Veldhuis, P. R. Bar, G. A. Veldink, J. F. G. Vliegenthart, and K. Nicolay Neuroprotection by {Delta}9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity J. Neurosci., September 1, 2001; 21(17): 6475 - 6479. [Abstract] [Full Text] [PDF]

				B. Moesgaard, G. Petersen, J. W. Jaroszewski, and H. S. Hansen Age dependent accumulation of N-acyl-ethanolamine phospholipids in ischemic rat brain: a 31P NMR and enzyme activity study J. Lipid Res., June 1, 2000; 41(6): 985 - 990. [Abstract] [Full Text]

				T. Nagayama, A. D. Sinor, R. P. Simon, J. Chen, S. H. Graham, K. Jin, and D. A. Greenberg Cannabinoids and Neuroprotection in Global and Focal Cerebral Ischemia and in Neuronal Cultures J. Neurosci., April 15, 1999; 19(8): 2987 - 2995. [Abstract] [Full Text] [PDF]

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