cannabidiol and Infarction--Middle-Cerebral-Artery

Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 μM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin's detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg

Topics: Animals; Apoptosis; Brain Ischemia; Cannabidiol; Glucose; GTP Phosphohydrolases; Infarction, Middle Cerebral Artery; Male; Mitochondrial Proteins; Neuroprotection; Neuroprotective Agents; Oxygen; Rats; Reperfusion Injury; Ubiquitin-Protein Ligases

Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer. CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke. In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion. These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R

Topics: Animals; Anticonvulsants; Cannabidiol; Disease Models, Animal; Infarction, Middle Cerebral Artery; Male; Mice, Knockout; Morphine; N-Methylaspartate; Nociception; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Seizures; Sigma-1 Receptor; Stroke

Stroke is a neurological disease, which, in addition to high mortality, imposes many financial and mental burdens on families and the society. The main objective of this study was to investigate the effect of cannabidiol (CBD) on one of the major inflammatory pathways in cerebral ischaemia.. Using stereotaxic surgery, the cannula was implanted into the right lateral ventricle of rats. CBD (50, 100, and 200 ng/rat; i.c.v.) was administrated for five consecutive days. After pretreatment, the rats were subjected to 60 min of right middle cerebral artery occlusion (MCAO). After 24 h, neurological deficits score, infarct volume, brain oedema, and blood-brain barrier (BBB) permeability in total, core, and penumbra areas were assessed. The expression of tumour necrosis factor alfa (TNF-α), tumour necrosis factor receptor 1 (TNFR1), and nuclear factor-kappa B (NF-кB) in the mentioned regions was also studied.. Administration of CBD (100 and 200 ng/rat) caused a significant reduction in infarction, brain oedema, and BBB permeability compared with the vehicle-received group. Down-regulation of TNF-α, TNFR1, and NF-кB expression was also observed by CBD.. The results achieved in this study support the idea that CBD has a cerebroprotective effect (partly through suppression of TNF-α, TNFR1, and NF-кB) on ischaemic injury.. CBD, cannabidiol; ANOVA, analysis of variance; PVDF, polyvinylidene difluoride; SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; SEM, standard error of mean.

Topics: Animals; Blood-Brain Barrier; Brain Infarction; Cannabidiol; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Infarction, Middle Cerebral Artery; Infusions, Intraventricular; Ischemic Attack, Transient; Male; Neurologic Examination; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Tumor Necrosis Factor-alpha

We examined the cerebroprotective mechanism of cannabidiol, the non-psychoactive component of marijuana, against infarction in a 4-h mouse middle cerebral artery (MCA) occlusion model. Cannabidiol was intraperitoneally administrated immediately before and 3h after cerebral ischemia. Infarct size and myeloperoxidase (MPO) activity, a marker of neutrophil, monocyte/macropharge, were measured at 24h after cerebral ischemia. Activated microglia and astrocytes were evaluated by immunostaining. Moreover, high-mobility group box1 (HMGB1) was also evaluated at 1 and 3 days after MCA occlusion. In addition, neurological score and motor coordination on the rota-rod test were assessed at 1 and 3 days after cerebral ischemia. Cannabidiol significantly prevented infarction and MPO activity at 20h after reperfusion. These effects of cannabidiol were not inhibited by either SR141716 or AM630. Cannabidiol inhibited the MPO-positive cells expressing HMGB1 and also decreased the expression level of HMGB1 in plasma. In addition, cannabidiol decreased the number of Iba1- and GFAP-positive cells at 3 days after cerebral ischemia. Moreover, cannabidiol improved neurological score and motor coordination on the rota-rod test. Our results suggest that cannabidiol inhibits monocyte/macropharge expressing HMGB1 followed by preventing glial activation and neurological impairment induced by cerebral ischemia. Cannabidiol will open new therapeutic possibilities for post-ischemic injury via HMGB1-inhibiting mechanism.

Topics: Analysis of Variance; Animals; Blood Pressure; Brain Injuries; Calcium-Binding Proteins; Cannabidiol; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Gene Expression Regulation; Glial Fibrillary Acidic Protein; HMGB1 Protein; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Male; Mice; Microfilament Proteins; Motor Activity; Neurologic Examination; Peroxidase; Phosphopyruvate Hydratase; Reperfusion; Tetrazolium Salts; Time Factors

Both Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol are known to have a neuroprotective effect against cerebral ischemia. We examined whether repeated treatment with both drugs led to tolerance of their neuroprotective effects in mice subjected to 4h-middle cerebral artery (MCA) occlusion. The neuroprotective effect of Delta(9)-THC but not cannabidiol was inhibited by SR141716, cannabinoid CB(1) receptor antagonist. Fourteen-day repeated treatment with Delta(9)-THC, but not cannabidiol, led to tolerance of the neuroprotective and hypothermic effects. In addition, repeated treatment with Delta(9)-THC reversed the increase in cerebral blood flow (CBF), while cannabidiol did not reverse that effect. Repeated treatment with Delta(9)-THC caused CB(1) receptor desensitization and down-regulation in MCA occluded mice. On the contrary, cannabidiol did not influence these effects. Moreover, the neuroprotective effect and an increase in CBF induced by repeated treatment with cannabidiol were in part inhibited by WAY100135, serotonin 5-HT(1A) receptor antagonist. Cannabidiol exhibited stronger antioxidative power than Delta(9)-THC in an in vitro study using the 1,1-diphenyl-2-picryhydrazyl (DPPH) radical. Thus, cannabidiol is a potent antioxidant agent without developing tolerance to its neuroprotective effect, acting through a CB(1) receptor-independent mechanism. It is to be hoped that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.

Topics: Analysis of Variance; Animals; Behavior, Animal; Body Temperature; Cannabidiol; Cerebral Infarction; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Dronabinol; Drug Administration Schedule; Drug Interactions; Drug Tolerance; Infarction, Middle Cerebral Artery; Male; Mice; Neuroprotective Agents; Piperazines; Piperidines; Pyrazoles; Rimonabant; Serotonin Antagonists; Time Factors

We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Release of glutamate in the cortex was measured at 2 h after MCA occlusion. Myeloperoxidase (MPO) and cerebral blood flow were measured at 1 h after reperfusion. In addition, infarct size and MPO were determined at 24 and 72 h after MCA occlusion. The neuroprotective effect of cannabidiol was not inhibited by either SR141716 or AM630. Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction. Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion. Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils. Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group. Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.

Topics: Animals; Behavior, Animal; Cannabidiol; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Functional Laterality; Glutamic Acid; Infarction, Middle Cerebral Artery; Male; Mice; Motor Activity; Neuroprotective Agents; Perfusion; Peroxidase; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Tetrazolium Salts; Time Factors

Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice.. Male MCA occluded mice were treated with cannabidiol, abnormal cannabidiol, anandamide, methanandamide, cannabidiol plus capsazepine, and cannabidiol plus WAY100135 before and 3 hours after MCA occlusion. The infarct size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Cerebral blood flow (CBF) was measured at, before and 1, 2, 3, and 4 hours after MCA occlusion.. Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume. Moreover, the neuroprotective effect of cannabidiol was inhibited by WAY100135, a serotonin 5-hydroxytriptamine1A (5-HT1A) receptor antagonist but not capsazepine a vanilloid receptor antagonist. Cannabidiol increased CBF to the cortex, and the CBF was partly inhibited by WAY100135 in mice subjected to MCA occlusion.. Cannabidiol and abnormal cannabidiol reduced the infarct volume. Furthermore, the neuroprotective effect of cannabidiol was inhibited by WAY100135 but not capsazepine, and the CBF increased by cannabidiol was partially reversed by WAY100135. These results suggested that the neuroprotective effect of cannabidiol may be related to the increase in CBF through the serotonergic 5-HT1A receptor.

Topics: Animals; Arachidonic Acids; Cannabidiol; Cerebral Infarction; Cerebrovascular Circulation; Endocannabinoids; Infarction, Middle Cerebral Artery; Male; Mice; Neuroprotective Agents; Piperazines; Polyunsaturated Alkamides; Receptor, Serotonin, 5-HT1A; Resorcinols; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists

Cannabidiol, a non-psychoactive constituent of cannabis, has been reported as a neuroprotectant. Cannabidiol and Delta(9)-tetrahydrocannabinol, the primary psychoactive constituent of cannabis, significantly decreased the infarct volume at 4 h in the mouse middle cerebral artery occlusion model. The neuroprotective effects of Delta(9)-tetrahydrocannabinol but not cannabidiol were inhibited by SR141716, a cannabinoid CB1 receptor antagonist, and were abolished by warming of the animals to the levels observed in the controls. Delta(9)-Tetrahydrocannabinol significantly decreased the rectal temperature, and the hypothermic effect was inhibited by SR141716. These results surely show that the neuroprotective effect of Delta(9)-tetrahydrocannabinol are via a CB1 receptor and temperature-dependent mechanisms whereas the neuroprotective effects of cannabidiol are independent of CB1 blockade and of hypothermia.

Topics: Analysis of Variance; Animals; Body Temperature; Brain Infarction; Cannabidiol; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Fever; Infarction, Middle Cerebral Artery; Male; Mice; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Tetrazolium Salts; Time Factors