The neuroprotective effect of lithium in cannabinoid dependence is mediated through modulation of cyclic AMP, ERK1/2 and GSK-3β phosphorylation in cerebellar granular neurons of rat

Authors

  • Ahmad Reza Dehpour Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Ali Razmi Pharmacology and Applied Medicine Department of Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
  • Hamid Reza Rahimi Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Mohammad Hossein Ghahremani Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Mohammad Sharifzadeh Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Seyed Nasser Ostad Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Shahram Ejtemaei-Mehr Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Abstract:

Lithium (Li), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has used to attenuate thecannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this areunclear. Recent studies indicate the involvement of upstream extracellular signal kinase1/2 (ERK1/2)and downstream GSK-3β pathways in the development of cannabinoid-induced dependence. Thisis mediated through cannabinoid receptor 1 (CB1) enriched in cerebellar granular neurons (CGNs).Accordingly, the present study aimed to investigate the mechanism of modulatory/neuroprotectiveeffects of Li on a cannabinoid agonist (WIN 55,212-2 (WIN))-induced dependence, throughquantitative analysis of some involved proteins such as ERK1/2, GSK-3β and related signalingpathways including their phosphorylated forms; and cAMP level as the other molecular mechanismsleading to dependence, in CGNs model. The CGNs were prepared from 7-day-old Wistar rat pup in a12-well plate, pretreated with Li (1mM) and an ERK1/2 inhibitor SL327 (SL, 10 μM). The WIN (1μM) was added 30 minutes prior to treatment and AM251 (AM, 1 μM), as a cannabinoid antagonistwas co-treated with WIN. The cAMP level, as an indicator of cannabinoid-induced dependence, wasmeasured by ELISA following forskolin (FSK) stimulation. Western blot analyses determined thephosphorylated forms of ERK1/2 (p-ERK1/2), GSK-3β (p-GSK-3β) as well as their total expressionsin various treatment times and doses in CGNs. WIN alone could down regulate the cAMP/p-ERK1/2cascade compared to AM treatment. However, P-GSK-3β was up-regulated with Li and WIN orwith SL and Li pretreatment to AM-induced cellular response, which was the highest 60 minutesafter CGNs exposure. Results further suggested the potential role of Li pretreatment to diminishthe development of cannabinoid-induced dependence/neuronal injury through possible mechanismsof modulating the cAMP/p-ERK1/2 cascade independent of p-GSK-3β signaling pathway in-vitro.

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the neuroprotective effect of lithium in cannabinoid dependence is mediated through modulation of cyclic amp, erk1/2 and gsk-3β phosphorylation in cerebellar granular neurons of rat

lithium (li), a glycogen synthase kinase-3β (gsk-3β) inhibitor, has used to attenuate thecannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this areunclear. recent studies indicate the involvement of upstream extracellular signal kinase1/2 (erk1/2)and downstream gsk-3β pathways in the development of cannabinoid-induced dependence. thisis mediated through cannab...

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The Neuroprotective Effect of Lithium in cannabinoid Dependence is Mediated through Modulation of Cyclic AMP, ERK1/2 and GSK-3β Phosphorylation in Cerebellar Granular Neurons of Rat

Lithium (Li), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has used to attenuate the cannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this are unclear. Recent studies indicate the involvement of upstream extracellular signal kinase1/2 (ERK1/2) and downstream GSK-3β pathways in the development of cannabinoid-induced dependence. This is mediated through ca...

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Journal title

volume 14  issue 4

pages  1123- 1135

publication date 2015-10-01

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