Effects of Lithium and Lamotrigine on Oxidative–Nitrosative Stress and Spatial Learning Deficit After Global Cerebral Ischemia

Abstract

Lithium (Li) and lamotrigine (LTG) have neuroprotective properties. However, the exact therapeutic mechanisms of these drugs have not been well understood. We investigated the antioxidant properties of Li (40 and 80 mg/kg/day) and LTG (20 and 40 mg/kg/day) in a rat model of global cerebral ischemia based on permanent bilateral occlusion of the common carotid arteries (BCAO). Nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione reductase (GSH-R), catalase (CAT) and superoxide dismutase (SOD) levels were measured as an indicator of oxidative-nitrosative stress in both prefrontal cortex (PFC) and hippocampus after 28 days of treatment. The spatial learning disability was also assessed at the end of the study by Morris water maze (MWM) test. All oxidative-nitrosative parameters were found to be higher in the groups under treatment than in sham. Both drugs caused a decrease in PFC NO and MDA elevation, meanwhile the increase in GSH, GSH-R, CAT and SOD levels was significantly more evident in treated groups. We also found higher PFC GSH-R and hippocampal SOD levels in BCAO + Li (80 mg/day) treated group when compared with BCAO + LTG 40 mg/day. MWM test data showed a similar increase in spatial learning ability in all groups under treatment. We found no other statistical difference in comparison of treated groups with different dosages. Our findings suggested that Li and LTG treatments may decrease spatial learning memory deficits accompanied by lower oxidative-nitrosative stress in global cerebral ischemia. Both drugs may have potential benefits for the treatment of vascular dementia in clinical practice.

Effects of High-Fat Diet on Neuronal Damage, Gliosis, Inflammatory Process and Oxidative Stress in the Hippocampus Induced by Transient Cerebral Ischemia

“…Among susceptible brain regions, the hippocampus is known as the most vulnerable region to cerebral ischemia, and extensive neuronal death occurs in this region [1][2][3][4]. In the hippocampus, pyramidal neurons of the CA1 region undergo neuronal death/ degeneration some days after the initial ischemic insult, which is referred to as ''delayed neuronal death'' [5].…”

Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial

“…12 Interestingly, cellular and animal models suggest that lamotrigine has neuroprotective effects, mediated by reductions in oxidative stress. [13][14][15] These findings are notable given evidence for increased oxidative stress in patients with bipolar disorder. 16,17 Given that the lamotrigine−FA interaction was unexpected, this aspect of the results of CEQUEL should be treated with caution.…”

“…In contrast, lamotrigine has multiple pharmacological actions and, although its anticonvulsant actions may result from its blockade of voltage‐gated sodium channels, it is unclear which of these are relevant for its efficacy in bipolar disorder . Interestingly, cellular and animal models suggest that lamotrigine has neuroprotective effects, mediated by reductions in oxidative stress . These findings are notable given evidence for increased oxidative stress in patients with bipolar disorder …”

Effect on intensity of treadmill running on learning, memory and expressions of cell cycle-related proteins in rats with cerebral ischemia

“…Ischemic cerebrovascular disease has a high incidence, high mortality and high disability rate, posing great threat to human health [1] and leading to movement disorder and decline in learning performance [2]. Hippocampus is an important part of learning and memory of high-level nervous activity.…”