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Rahimi HR, Ghahremani MH, Dehpour AR, et al. 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. Iran J Pharm Res. 2015;14(4):1123-35
Rahimi, H. R., Ghahremani, M. H., Dehpour, A. R., Sharifzadeh, M., Ejtemaei-Mehr, S., Razmi, A., & Ostad, S. N. (2015). 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. Iranian journal of pharmaceutical research : IJPR, 14(4), 1123-35.
Rahimi, Hamid Reza, et al. "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." Iranian journal of pharmaceutical research : IJPR vol. 14,4 (2015): 1123-35.
Rahimi HR, Ghahremani MH, Dehpour AR, Sharifzadeh M, Ejtemaei-Mehr S, Razmi A, Ostad SN. 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. Iran J Pharm Res. 2015;14(4):1123-35. PMID: 26664379; PMCID: PMC4673940.
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Iran J Pharm Res. 2015;14(4):1123-35.

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.

Iranian journal of pharmaceutical research : IJPR

Hamid Reza Rahimi, Mohammad Hossein Ghahremani, Ahmad Reza Dehpour, Mohammad Sharifzadeh, Shahram Ejtemaei-Mehr, Ali Razmi, Seyed Nasser Ostad

Affiliations

  1. Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. ; PharmaceuticsResearch Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran. ; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
  2. Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
  3. Experimental Medicine Research Center, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences,Tehran, Iran.
  4. Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj,Iran.

PMID: 26664379 PMCID: PMC4673940

Abstract

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 cannabinoid receptor 1 (CB1) enriched in cerebellar granular neurons (CGNs). Accordingly, the present study aimed to investigate the mechanism of modulatory/neuroprotective effects of Li on a cannabinoid agonist (WIN 55,212-2 (WIN))-induced dependence, through quantitative analysis of some involved proteins such as ERK1/2, GSK-3β and related signaling pathways including their phosphorylated forms; and cAMP level as the other molecular mechanisms leading to dependence, in CGNs model. The CGNs were prepared from 7-day-old Wistar rat pup in a 12-well plate, pretreated with Li (1mM) and an ERK1/2 inhibitor SL327 (SL, 10 µM). The WIN (1 µM) was added 30 minutes prior to treatment and AM251 (AM, 1 µM), as a cannabinoid antagonist was co-treated with WIN. The cAMP level, as an indicator of cannabinoid-induced dependence, was measured by ELISA following forskolin (FSK) stimulation. Western blot analyses determined the phosphorylated forms of ERK1/2 (p-ERK1/2), GSK-3β (p-GSK-3β) as well as their total expressions in various treatment times and doses in CGNs. WIN alone could down regulate the cAMP/p-ERK1/2 cascade compared to AM treatment. However, P-GSK-3β was up-regulated with Li and WIN or with SL and Li pretreatment to AM-induced cellular response, which was the highest 60 minutes after CGNs exposure. Results further suggested the potential role of Li pretreatment to diminish the development of cannabinoid-induced dependence/neuronal injury through possible mechanisms of modulating the cAMP/p-ERK1/2 cascade independent of p-GSK-3β signaling pathway in-vitro.

Keywords: 212-2; Cerebellar granular neurons; Cyclic AMP; Dependence; In-vitro; WIN 55

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