Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling

Abstract

SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…19,25 Briefly, after decapitation, brains were rapidly removed and placed in cold oxygenated (95% O 2 , 5% CO 2 ) artificial cerebrospinal fluid (ACSF) containing (mM) 125.0 NaCl, 2.5 KCl, 1.0 MgCl 2 , 25.0 NaHCO 3 , 1.25 NaH 2 PO 4 , 2.0 CaCl 2 , 25.0 glucose, 3 pyruvic acid and 1 ascorbic acid. Slices were cut at a thickness of 350 to 400 μm and transferred to a holding chamber in an incubator containing ACSF at 36°C for 0.5 to 1 hour, and maintained in an incubator containing oxygenated ACSF at room temperature (~22 to 24°C) for 41.5 hours before recordings.…”

“…Long-term potentiation (LTP) at CA3-CA1 synapses was induced by high-frequency stimulation, as described previously. 19,25 The input-output function was tested before recording LTP, and the baseline stimulation strength was set to provide field excitatory postsynaptic potential with an amplitude of~30% from the subthreshold maximum derived from the input-output function.…”

“…19,20,25 Cortical and hippocampal tissues were extracted and immediately homogenized in RIPA lysis buffer and protease inhibitors, and incubated on ice for 30 minutes, then centrifuged for 10 minutes at 10,000 r.p.m. at 4°C.…”

“…Band densities were normalized to the total amount of protein loaded in each well as determined by mouse anti-β-actin (1:4,000, Sigma, St Louis, MO, USA), as described previously. 19,20,25 Reverse Transcription and Real-Time PCR Total RNA was prepared from harvested tissue with the RNeasy Mini Kit (Qiagen) and treated with RNase-free DNase (Qiagen) according to the manufacturer's instructions. The RNA concentration was measured by a spectrophotometer (DU 640; Beckman, Brea, CA, USA).…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…Beneficial effects in preclinical studies involved CB 1 R and/or CB 2 R, the selective activation of which was found to be effective in improving cognitive impairment, preserving neuronal cells, and preventing Aβ-induced microglial activation and the generation of proinflammatory mediators, as well as removing pathological deposits in different in vivo and in vitro models of AD [86][87][88][89][90]. In addition, beneficial effects of cannabinoids in AD may also be, at least partially, related to the activation of PPAR nuclear receptors for which certain cannabinoids may serve as ligands [88,91], whereas, in the case of some particular cannabinoids (e.g., antioxidant phytocannabinoids), they may exert some more specific effects in relation with AD pathogenesis, for example: 1) by preventing Aβ aggregation, thereby hindering plaque formation and reducing the density of neuritic plaques due to inhibition of acetylcholinesterase activity or increased expression of neprilysin, an enzyme in the Aβ degradation cascade [86,[91][92][93][94]; and 2) by inhibiting Aβ-induced tau protein hyperphosphorylation by glycogen synthase kinase-3β [82][83][84]. Some recent studies have also highlighted the interest of targeting endocannabinoid inactivation in AD, through strategies of genetic inactivation [e.g., mice deficient in monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH)] or by inhibiting these enzymes (e.g., JZL184, URB597, respectively) [95][96][97][98].…”