Phosphorylation of PI3K/Akt at Thr308, but not MAPK kinase, mediates lithium-induced neuroprotection against cerebral ischemia in mice

Exp Neurol. 2022 Feb 2:113996. doi: 10.1016/j.expneurol.2022.113996. Online ahead of print.ABSTRACTLithium, in addition to its effect on acute and long-term bipolar disorder, is involved in neuroprotection after ischemic stroke. Yet, its mechanism of action is still poorly understood, which was only limited to its modulatory effect on GSK pathway. Therefore, we initially analyzed the dose-dependent effects of lithium on neurological deficits, infarct volume, brain edema and blood-brain barrier integrity, along with neuronal injury and survival in mice subjected to focal cerebral ischemia. Thereafter, we investigated the involvement of the PI3K/Akt and MEK signal transduction pathways and their components. Our observations revealed that 2 mmol/kg lithium significantly improved post-ischemic brain tissue survival. Although, 2 mmol/kg lithium had no negative effect on brain microcirculation, 5 and 20 mmol/kg lithium reduced brain perfusion. Furthermore, supratherapeutic dose of lithium in 20 mmol/kg lead to animal death. In addition, improvement of brain perfusion with L-arginine, did not change the effect of 5 mmol/kg lithium on brain injury. Additionally, post-stroke blood-brain barrier leakage, hemodynamic impairment and apoptosis have been reversed by lithium treatment. Interestingly, lithium-induced neuroprotection was associated with increased phosphorylation of Akt at Thr308 and suppressed GSK-3β phosphorylation at Ser9 residue. Lithium upregulated Erk-2 and downregulate...
Source: Experimental Neurology - Category: Neurology Authors: Source Type: research