minocycline and glyceryl-2-arachidonate

Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model.

Topics: Animals; Arachidonic Acids; Benzodioxoles; Brain; Brain Ischemia; Carbon Radioisotopes; Cell Hypoxia; Disease Models, Animal; Endocannabinoids; Glycerides; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Minocycline; Monoacylglycerol Lipases; Neuroprotective Agents; Piperidines; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Stroke; Tomography, X-Ray Computed

Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P < 0.001). Minocycline treatment also significantly attenuated OX-42 immunoreactivity, a marker of activated microglia, in the ipsilateral (P < 0.001) and contralateral (P < 0.01) spinal cord of SNL rats, compared to vehicle controls. Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord. Thus, activation of microglia affects spinal levels of endocannabinoids and related compounds in neuropathic pain states.

Topics: Amides; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cell Proliferation; Disease Models, Animal; Endocannabinoids; Ethanolamines; Glycerides; Microglia; Minocycline; Neuralgia; Palmitic Acids; Polyunsaturated Alkamides; Rats; Spinal Cord