|Abstract: ||Methamphetamine (METH) is a lipofilic molecule widely abused for its psychostimulant effects. Its long term use can result in neurotoxic and adverse consequences like activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrite, microglia stimulation, astrogliosis and hyperthermia [Maxwell JC and Brecht ML, 2011]. Notably, METH abusers also consume Cannabis [UNODC, 2013]. Several line of research have demonstrated that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 receptor agonists exert neuroprotective effects in different models of cerebral damage, including excitotoxic injury [Deng X and Cadet JL, 2009; La Voie MJ, et al. 2004]. In this study we evaluated the neuroprotective effect of Δ9-THC on an animal model of neurotoxicity induced by METH. Rats treated with a binge administation of METH (4 x 10 mg/Kg s.c. 2h apart), were pre-treated or post-treated with 1 mg/Kg or 3 mg/Kg of Δ9-THC (i.p) and sacrificed 3 days after the last METH administration. METH-induced nNOS overexpression and Glial Fibrillary Acidic Protein (GFAP)-immunoreactivity, markers of brain damage, were attenuated by treatment with Δ9-THC. In order to verify the role of CB1 receptor in the mechanism of Δ9-THC-neuroprotection, rats post-treated with Δ9-THC (1 mg/Kg) were pre-treated with the CB1 rceptor antagonist SR141716A (SR). SR partially blocked METH-induced nNOS-overexpression but failed to revert the decreasing effect of Δ9-THC on METH-induced GFAP-immunostaining. These results indicate that Δ9-THC reduces METH-induced brain damage by CB1-dependent and independent mechanisms.
In order to identify other neuroprotective mechanisms, we evaluated as markers of neurotoxicity: i) tyrosine hydroxilase (TH), marker of terminal loss; ii) ionized calcium binding adapter molecule 1 (IBA-1), marker of microglial activation; iii) brain derived neurotrophic factor (BDNF) and iiii) CB2 receptor. Post-treatment with Δ9-THC 1mg/Kg increase the METH-induced down-regulation of TH and counteract the IBA-1 over-expression induced by METH. On the contrary, it fails to revert the METH-induced BDNF-increase and CB2-increase. Further studies will be carried out to support the involvement of CB2 receptor on Δ9-THC-mediated mechanism of neuroprotection. References Deng X and Cadet JL (2000) Methamphetamine-induced apoptosis is attenuated in the striata of copper-zinc superoxide dismutase transgenic mice. Brain Res Mol Brain Res. 83: 121-124. LaVoie MJ, Card JP, Hasting TG (2004) Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity. Exp Neurol. 187: 47-57. Maxwell JC and Brecht ML (2011) Methamphetamine: here we go again? Addict Behav. 36: 1168–1173. United Nation Office on Drugs and Crime (UNODC) (2013) World Drug Report 2013 (United Nations publication, Sales No. E.13.XI.6).|