Molecular targets of lithium action

Abstract

Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1).

Lithium Attenuates Peripheral Neuropathy Induced by Paclitaxel in Rats

“…Our finding was similar to the Petrini et al [13] findings showing that lithium at therapeutic doses can ameliorate vincristine neuropathy. It is widely accepted that lithium robustly protects neurons against excitotoxicity mediated by NMDA receptors [9,30]. Boyle et al [31] showed that glutamate can significantly prevent or ameliorate sensorimotor neuropathy induced by either vincristine or paclitaxel.…”

“…Thus, microtubules interfering agents like vincristine or paclitaxel may disturb non-neoplastic cells such as nerves and finally cause apoptosis. Hence, peripheral neuropathy is one of the most frequent side effects of these two drugs that usually result in dose modification and changes in the treatment plan [5][6][7][8].As a mood stabilizer, lithium is commonly prescribed for bipolar disorders, and although its mechanism of action remains unknown, it is well established that lithium exerts some of its therapeutic effects through G-protein-coupled pathway, glycogen synthase kinase-3 (GSK3b), inositol monophopsphate and nitric oxide-dependent pathways and augmentation of serotonin function in the central nervous system [9,10]. Previous studies have reported that lithium has neuroprotective effects.…”

“…As a mood stabilizer, lithium is commonly prescribed for bipolar disorders, and although its mechanism of action remains unknown, it is well established that lithium exerts some of its therapeutic effects through G-protein-coupled pathway, glycogen synthase kinase-3 (GSK3b), inositol monophopsphate and nitric oxide-dependent pathways and augmentation of serotonin function in the central nervous system [9,10]. Previous studies have reported that lithium has neuroprotective effects.…”

Inhibitors of Brain Phospholipase A2Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

“…It has been used for the treatment of bipolar disorders for almost a halfcentury (Corbella and Vieta, 2003). Lithium ion has a neuroprotective effect on brain tissue.…”

Prefrontal gray matter increases in healthy individuals after lithium treatment: A voxel-based morphometry study

“…It affects multiple cellular signaling pathways in the brain [1] and has neurotrophic and neuroprotective effects [2]. Studies utilizing anatomical region-of-interest [3,4] and cortical pattern matching [5] methods, as well as neurochemical imaging [6], demonstrated detectable brain changes related to lithium treatment in bipolar patients.…”