“Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates. We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats. The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ. Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.” https://www.ncbi.nlm.nih.gov/pubmed/28691158 http://onlinelibrary.wiley.com/doi/10.1111/epi.13842/abstract]]>
Category Archives: Endocannabinoid System
Anti-inflammatory ω-3 endocannabinoid epoxides.
“Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA-derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides’ physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/28687674
http://www.pnas.org/content/early/2017/07/06/1610325114
“Omega-3 fatty acids fight inflammation via cannabinoids” https://www.sciencedaily.com/releases/2017/07/170718142909.htm
Polyunsaturated fatty acids and endocannabinoids in health and disease.
“Polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs). They mediate significant effects in the fine-tune adjustment of body homeostasis. Phyto- and synthetic cannabinoids also rule the daily life of billions worldwide, as they are involved in obesity, depression and drug addiction. Consequently, there is growing interest to reveal novel active compounds in this field. Cloning of cannabinoid receptors in the 90s and the identification of the endogenous mediators arachidonylethanolamide (anandamide, AEA) and 2-arachidonyglycerol (2-AG), led to the characterization of the endocannabinoid system (ECS), together with their metabolizing enzymes and membrane transporters. Today, the ECS is known to be involved in diverse functions such as appetite control, food intake, energy balance, neuroprotection, neurodegenerative diseases, stroke, mood disorders, emesis, modulation of pain, inflammatory responses, as well as in cancer therapy. Western diet as well as restriction of micronutrients and fatty acids, such as DHA, could be related to altered production of pro-inflammatory mediators (e.g. eicosanoids) and ECs, contributing to the progression of cardiovascular diseases, diabetes, obesity, depression or impairing conditions, such as Alzheimer’ s disease. Here we review how diets based in PUFAs might be linked to ECS and to the maintenance of central and peripheral metabolism, brain plasticity, memory and learning, blood flow, and genesis of neural cells.”
https://www.ncbi.nlm.nih.gov/pubmed/28686542
http://www.tandfonline.com/doi/abs/10.1080/1028415X.2017.1347373?journalCode=ynns20
“Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the 
“Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (