Pharmacological evidence for lithium-induced neuroprotection against methamphetamine-induced neurodegeneration via Akt-1/GSK3 and CREB-BDNF signaling pathways

Abstract

Objectives: Neurodegeneration is an outcome of Methamphetamine (METH) abuse. Studies have emphasized on the neuroprotective properties of lithium. The current study is designed towards evaluating the role of Akt-1/GSK3 and CREB-BDNF signaling pathways in mediating lithium neuroprotection against METH-induced neurodegeneration in rats.

Materials and methods: Sixty adult male rats were randomly divided into five groups: control group (received 0.7 ml normal saline per rat for 28 days), METH group (given 10 mg/kg of METH intraperitoneally for 28 days), groups 3, 4, and 5 (given METH (10 mg/kg) and lithium (75, 150, and 300 mg/kg intraperitoneally, individually for 28 days). Morris water maze (MWM) was used to assess mental functions. In addition to hippocampal neurodegeneration, Brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Glycogen synthase kinase 3 (GSK3), and Protein kinase B (Akt-1) were assessed in isolated hippocampus.

Results: METH abuse caused marked disorders in learning and memory that were dramatically improved with various doses of lithium. Furthermore, METH increased lipid peroxidation and the levels of oxidized form of interleukin 1 beta (IL-1β), glutathione (GSSG), Bax, tumor necrosis factor alpha (TNF-α), and GSK3, while attenuating the extent of glutathione (reduced form (GSH)), P-CREB, Bcl-2, BDNF, and Akt-1 in the hippocampus. Moreover, METH declined superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx) activity in the hippocampus. Conversely, lithium attenuated METH-stimulated apoptosis, oxidative stress, and inflammation; while improving the extent of BDNF and P-CREB.

Conclusion: Probably lithium possesses neuroprotection against METH-stimulated neurodegeneration in the hippocampus via Akt-1/GSK3β and CREB/BDNF signaling pathways.

Keywords: Akt; BDNF; CREB; GSK3; Lithium; Methamphetamine.

Figure 1

Learning and memory assessment by using Morris Water Maze (MWM). (A) average escape latency, (B) average distance traveled, (C) average swimming speed, and (D) percentage of time spent in target quadrant in probe trial in control group and groups treated with 10 mg/kg of methamphetamine and 10 mg/kg of methamphetamine in combination with lithium with doses of 75, 150, and 300 mg/kg across all training

Figure 2

Effects of various doses of lithium (75, 150, and 300 mg/kg) on methamphetamine-induced s in (A) TNF-α and (B) IL-1β level in rat isolated hippocampus. All data are expressed as mean ± SEM (n=8). ### P<0.001 vs control; *** P<0.001 vs 10 mg/kg of methamphetamine

Figure 3

Effects of various doses of lithium (75, 150, and 300 mg/kg) on methamphetamine-induced alterations in protein expression of (A) Bax, (B) Bcl-2, (C) BDNF total, (D) CREB, (E) phosphorylated CREB , (F) total Akt-1, (G) phosphorylated Akt-1, (H) total GSK3, and (I) phosphorylated GSK3 in rat isolated hippocampus