jzl-184 and Brain-Ischemia

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.. SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests.. 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.

Topics: Animals; Benzodioxoles; Brain Ischemia; Carbamates; Disease Models, Animal; Enzyme Inhibitors; Male; Monoacylglycerol Lipases; Neuroprotective Agents; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Succinimides

Investigators are searching to find new therapeutic strategies to reduce stroke secondary injury. JZL-184 (JZL) is an inhibitory factor for production of arachidonic acid (AA). Thus, it suppresses production of AA metabolites which are the cause of inflammation and tissue edema. Therefore, JZL may be considered for suppression of stroke secondary injury in mice middle cerebral artery occlusion (MCAO) model. Additionally, Aspirin is a known anti-inflammatory factor which is used to reduce pro-inflammatory secondary injury. The aim of this study was to determine the effects of JZL on the reduction of stroke secondary injury and to compare them with Aspirin effects.. MCAO model has been induced and accordingly 83 male MCAO induced mice have been introduced to the study. The animals were divided to seven groups including intact, controls, vehicle, Aspirin, JZL 4, 8 and 16 mg/kg administrated groups. Brain edema and infarction, behavioral functions and brain levels of IL-10, TNF-α and matrix metaloperoteinase-9 (MMP9) have been examined in the evaluated groups.. The results revealed that JZL reduced brain edema, infarction, brain levels of TNF-α and MMP9 and also increased brain levels of IL-10 as well as improved behavioral functions in all three concentrations. The therapeutic effects of JZL were observed as well as Aspirin.. Based on the results, it seems that JZL can be considered as a good candidate for inhibition of stroke secondary injury in the case of delayed treatment.

Topics: Animals; Aspirin; Behavior, Animal; Benzodioxoles; Brain; Brain Edema; Brain Ischemia; Disease Models, Animal; Edema; Infarction, Middle Cerebral Artery; Inflammation; Interleukin-10; Male; Matrix Metalloproteinase 9; Mice; Monoacylglycerol Lipases; Neuroprotective Agents; Piperidines; Stroke; Tumor Necrosis Factor-alpha