Tag Archives: neuroprotection
Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.
“MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia.
Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors.
Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.”
https://www.ncbi.nlm.nih.gov/pubmed/29440474 http://stroke.ahajournals.org/content/early/2018/02/12/STROKEAHA.117.019664]]>Long-term depression induced by endogenous cannabinoids produces neuroprotection via astroglial CB1R after stroke in rodents.
“Ischemia not only activates cell death pathways but also triggers endogenous protective mechanisms. However, it is largely unknown what is the essence of the endogenous neuroprotective mechanisms induced by preconditioning. In this study we demonstrated that systemic injection of JZL195, a selective inhibitor of eCB clearance enzymes, induces in vivo long-term depression at CA3-CA1 synapses and at PrL-NAc synapses produces neuroprotection. JZL195-elicited long-term depression is blocked by AM281, the antagonist of cannabinoid 1 receptor (CB1R) and is abolished in mice lacking cannabinoid CB1 receptor (CB1R) in astroglial cells, but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. Blocking the glutamate NMDA receptor and the synaptic trafficking of glutamate AMPA receptor abolishes both long-term depression and neuroprotection induced by JZL195. Mice lacking CB1R in astroglia show decreased neuronal death following cerebral ischemia. Thus, an acute elevation of extracellular eCB following eCB clearance inhibition results in neuroprotection through long-term depression induction after sequential activation of astroglial CB1R and postsynaptic glutamate receptors.”
https://www.ncbi.nlm.nih.gov/pubmed/29432698
http://journals.sagepub.com/doi/abs/10.1177/0271678X18755661?journalCode=jcba
Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis.
“Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production.” https://aggregator.leafscience.org/role-for-neuronal-nitric-oxide-synthase-in-cannabinoid-induced-neurogenesis/
“Nitric oxide negatively regulates mammalian adult neurogenesis.” http://www.pnas.org/content/100/16/9566.long
“Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO.” http://jpet.aspetjournals.org/content/jpet/319/1/150.full.pdf]]>Acute ethanol inhibition of adult hippocampal neurogenesis involves CB1 cannabinoid receptor signaling.
“Chronic ethanol exposure has been found to inhibit adult hippocampal neurogenesis in multiple models of alcohol addiction. Together, these findings suggest that acute CB1R cannabinoid receptor activation and binge ethanol treatment reduce neurogenesis through mechanisms involving CB1R. ” https://www.ncbi.nlm.nih.gov/pubmed/29417597 http://onlinelibrary.wiley.com/doi/10.1111/acer.13608/abstract “Alcohol-induced neurodegeneration” http://www.diva-portal.org/smash/record.jsf?pid=diva2%3A666727&dswid=174
“Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice. Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain.” http://molpharm.aspetjournals.org/content/66/2/204.full
“Activation of Type 1 Cannabinoid Receptor (CB1R) Promotes Neurogenesis in Murine Subventricular Zone Cell Cultures” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660454/
“Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases” https://www.ncbi.nlm.nih.gov/pubmed/27364363 “The endocannabinoid system and neurogenesis in health and disease.” https://www.ncbi.nlm.nih.gov/pubmed/17404371“The role of cannabinoids in adult neurogenesis. Pharmacological targeting of the cannabinoid system as a regulator of neurogenesis may prove a fruitful strategy in the prevention or treatment of mood or memory disorders.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543605/
“Regulation of Adult Neurogenesis by Cannabinoids” https://www.researchgate.net/publication/264424221_Regulation_of_Adult_Neurogenesis_by_Cannabinoids
“Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats. Administration of ∆9-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.” https://www.ncbi.nlm.nih.gov/pubmed/28933048
“Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement. CBD was observed to stimulate hippocampal neurogenesis.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230631/
“Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Chronic administration of the major drugs of abuse including opiates, alcohol, nicotine, and cocaine has been reported to suppress hippocampal neurogenesis in adult rats. Plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis. Cannabinoids appear to be the only illicit drug whose capacity to produce increased hippocampal newborn neurons is positively correlated with its anxiolytic- and antidepressant-like effects. In summary, since adult hippocampal neurogenesis is suppressed following chronic administration of opiates, alcohol, nicotine, and cocaine, the present study suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic administration.” https://www.jci.org/articles/view/25509
]]>
The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.
“Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The present study revealed an upregulated endocannabinoid system in dogs with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.” https://www.ncbi.nlm.nih.gov/pubmed/29408878 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187197]]>
Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: reversal by cannabidiol.
“Evidence has demonstrated iron accumulation in specific brain regions of patients suffering from neurodegenerative disorders, and this metal has been recognized as a contributing factor for neurodegeneration.
Using an experimental model of brain iron accumulation, we have shown that iron induces severe memory deficits that are accompanied by oxidative stress, increased apoptotic markers, and decreased synaptophysin in the hippocampus of rats.
The present study aims to characterize iron loading effects as well as to determine the molecular targets of cannabidiol (CBD), the main non-psychomimetic compound of Cannabis sativa, on mitochondria.
Rats received iron in the neonatal period and CBD for 14 days in adulthood. Iron induced mitochondrial DNA (mtDNA) deletions, decreased epigenetic modulation of mtDNA, mitochondrial ferritin levels, and succinate dehydrogenase activity.
CBD rescued mitochondrial ferritin and epigenetic modulation of mtDNA, and restored succinate dehydrogenase activity in iron-treated rats.
These findings provide new insights into molecular targets of iron neurotoxicity and give support for the use of CBD as a disease modifying agent in the treatment of neurodegenerative diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/29374603