Free and Bound Therapeutic Lithium in Brain Signaling
Lithium has remained the first-line therapy for bipolar disorder for ~50 years, yet the exact molecular mechanism of its therapeutic action remains unclear. The existing biological hypotheses are based largely on lithium acting as a free cation. We propose that lithium’s multifaceted activities can be explained by considering its interactions as a free monocation competing with native cations in proteins as well as as a phosphate-bound polyanionic complex modulating the host protein function.
Lithium ion (Li+), a first-line therapy for bipolar disorder, is effective in preventing suicide and new depressive/manic episodes. Recently, it is also considered for treating traumatic brain injury and various neurodegenerative conditions including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Lithium’s therapeutic action is highly complex, inducing multiple effects on gene expression, neurotransmitter/receptor-mediated signaling, circadian regulation, and ion transport. Yet, how this beguilingly simple monocation with only two electrons could yield such profound therapeutic effects remains unclear. Various proposed modes of lithium’s therapeutic action suggest that lithium’s effects are mostly related to its interactions with native cations, especially Na+ and Mg2+, in various signaling proteins and organic cofactors.
We addressed the following aspects of lithium’s therapeutic actions:
Unlike drugs that exist in one form and act on a specific target, lithium exists in both free and bound forms and acts on multiple targets. We propose a unifying physicochemical basis that underlies lithium’s multifaceted effects by considering its interactions as a free monocation with native cations or as a phosphate-bound polyanionic complex modulating the host protein function. An in-depth understanding of lithium’s mechanisms of actions would help to develop better treatments limiting its adverse side effects and to repurpose lithium for treating other diseases such as traumatic brain injury and chronic neurodegenerative.