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https://www.ncbi.nlm.nih.gov/pubmed/9653176:  The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (-)Delta9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-D-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247568:  Cerebral ischemia is a common cause of death worldwide, after cardiovascular diseases and cancer, and its prevalence increases with increasing age [16]. The consequences of transient cerebral ischemia are often severe and have selectively harmful effects on the vulnerable regions involving the pyramidal neurons of the CA1 hippocampus [17]. Therefore, it is necessary to determine the underlying mechanism of cerebral ischemia/reperfusion injury and to develop effective strategies to circumvent this pathological condition. Oxygen–glucose deprivation/reperfusion is an in vitro model that mimics in vivo ischemia/reperfusion injury and initiates a series of devastating cascades that lead to the overproduction of ROS, the excessive release of excitatory amino acids, disturbance of the ionic balance, the overexpression of proapoptotic factors, the stimulation of a serious inflammatory response, and damage to mitochondrial functions [18], [19]. CBD is a nonpsychoactive component of marijuana, which exerts potent antioxidant and anti-inflammatory effects in vivo and in vitro. It is considered to have a neuroprotective property that is independent of the cannabinoid 1 and 2 receptors [4], [20]. Here, we demonstrate for the first time the potent neuroprotective effects of CBD against OGD/R-injury-induced cytotoxicity, energy crisis, and disturbance of the cellular metabolism by its: (i) attenuation of oxidative stress; (ii) enhancement of mitochondrial bioenergetics; and (iii) activation of the pentose- phosphate pathway to compensate for the diminished antioxidant defenses under stress conditions.

Consistent with many previous studies, cerebral ischemia/reperfusion significantly elevated the ROS content and reduced the antioxidant enzyme activities of neurons, causing oxidative damage and cell death [21], [22]. MDA, a product of lipid peroxidation, is a common and important marker of oxidative stress, which is markedly influenced by the excessive generation of ROS. Cells also have antioxidant defense mechanisms that involve enzymatic components such as GPx and SOD1, and nonenzymatic mechanisms, such as GSH. GSH, SOD1, and GPx act as endogenous free-radical scavengers, whereas GPx also functions biochemically to reduce lipid hydroperoxides to the corresponding alcohols [23]. In this study, OGD/R injury in HT22 cells caused excessive mitochondrial ROS generation, elevated MDA levels, and reductions in the GPx and SOD1 activities and the GSH content. After CBD treatment during the reperfusion period, the levels of mitochondrial ROS and MDA were dramatically reduced, simultaneously with the significant upregulation of GSH and increases in SOD1 and GPx activities. This suggests that neuroprotection is afforded by CBD by reducing the oxidative stress produced under OGD/R conditions. These results are consistent with the attenuation of oxidative damage by CBD in a diabetic retinopathy model [24], in PC12 cells stimulated with β-amyloid [9], and in oligodendrocyte progenitor cells treated with H2O2[8], and with the antioxidant property of CBD in rats with renal ischemia/reperfusion injury [25]. Furthermore, consistent with previous studies [26], [27], [28], we found that OGD/R insult markedly reduced cell viability and induced apoptosis and PARP-dependent cell death, which were significantly attenuated by the administration of CBD.

Mitochondria are the important energy production centers in neurons under physiological conditions, so mitochondrial dysfunction strongly affects neuronal function and survival [29]. A devastating well-known consequence of reperfusion following brain ischemia is grossly enhanced ROS production, followed by severe oxidative stress, which leads to mitochondrial dysfunction. Emerging evidence also suggests that substantially decreasing activities of mitochondrial complexes I and IV followed by irreversible impaired mitochondrial function and a consequently deficient energy supply often occur in the later stages of reperfusion [3], [30]. Moreover, the cerebral ischemia/reperfusion injury also results in delayed neuronal death after reperfusion by releasing apoptogenic factors, including cytochrome C (Cytc) and apoptosis inducing factor (AIF) from mitochondria [31], [32]. According to our OCR data, CBD attenuates the reduction of ATP production-linked OCR and the diminished mitochondrial capacity induced by OGD/R. This is consistent with previous studies that demonstrated that CBD modulates mitochondrial function and biogenesis to protect against doxorubicin-induced cardiomyopathy12; increases the activity of mitochondrial complexes in the rat brain [33]; exerts neuroprotective effects against mitochondrial toxins, and restores intracellular Ca2+ homeostasis in human neuroblastoma cell lines (SH-SY5Y)[34]. Taken together, these data suggest that CBD is a mitochondria-targeting drug that markedly enhances mitochondrial function and bioenergetics, thus exerting potent protective effects against pathological conditions.

Glucose, which is widely thought to be the vital oxidative substrate providing energy to the brain, can be further metabolized by glycolysis or the pentose-phosphate pathway (PPP) after phosphorylating glucose to glucose-6-phate (G6P) by hexokinase [35]. The two pathways share common pools of fructose-6-phosphate and glyceraldehyde-3-phosphate, and both produce pyruvate, which is converted to acetyl-coenzyme A and is fully oxidized through the tricarboxylic acid (TCA) cycle, contributing to energy conservation [36], [37]. Supporting the involvement of CBD in the regulation of glucose metabolism, we found that OGD/R injury moderately stimulated the glucose metabolism in hippocampal neurons, and that CBD supplementation during reperfusion induced greater glucose consumption and lactate release, implying that the stimulation of glucose metabolism by CBD protects hippocampal neurons from energy stress. As we know, neurons are particularly vulnerable to oxidative stress because their antioxidant defenses are weak and their ability to maintain energy homeostasis is poor [38]. Emerging evidence also indicates that neurons have a low capacity to metabolize glucose via glycolysis because they have low levels of PFKFB-3, an enzyme that supports the equilibrium between glycolysis and the pentose-phosphate pathway. Neurons are also more likely to utilize G6P through the pentose-phosphate pathway under oxidative stress, allowing the efficient regeneration of NADPH and the reduction of glutathione disulfide (GSSG) to GSH, which enhances the antioxidant defense system [36], [39], [40]. To further test whether the stimulation of the pentose-phosphate pathway is involved in neuronal glucose metabolism under OGD/R stress, the NADPH/NADP+ ratio and the activity of G6PDH, a rate-limiting enzyme of the pentose-phosphate pathway, were measured. In OGD/R-injured neurons, CBD supplementation increased the G6PDH activity and maintained the NADPH/NADP+ ratio, implicating the activation of the pentose-phosphate pathway in the protection of hippocampal neurons by CBD under oxidative stress. Therefore, we propose, for the first time, that CBD stimulates glucose metabolism through the pentose-phosphate pathway to maintain the redox balance and energy conservation during neuronal ischemia/reperfusion injury.

​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20965:  The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (−)Δ9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-d-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-d-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or α-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.

Cannabis -vs- Stroke