Lithium has been used in the treatment of
bipolar disorders for decades, but the exact mechanisms of action remain elusive to this day. Recent evidence suggests that
lithium is critically involved in a variety of signaling pathways affecting apoptosis,
inflammation, and neurogenesis, all of which contributing to the complex pathophysiology of various neurological diseases. As a matter of fact, preclinical work reports both acute and long-term neuroprotection in distinct neurological disease models such as
Parkinson's disease,
traumatic brain injury,
Alzheimer's disease, and
ischemic stroke.
Lithium treatment reduces cell injury, decreases α
synuclein aggregation and
Tau protein phosphorylation, modulates
inflammation and even stimulates neuroregeneration under experimental conditions of
Parkinson's disease,
traumatic brain injury, and
Alzheimer's disease. The therapeutic impact of
lithium under conditions of
ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies, giving rise to a randomized double-blind clinical
stroke trial. The preclinic data revealed a
lithium-induced upregulation of
anti-apoptotic proteins such as
B-cell lymphoma 2,
heat shock protein 70, and activated
protein 1, resulting in decreased neuronal cell loss.
Lithium, however, does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the
RE1-silencing transcription factor. In line with this,
lithium treatment has been shown to modulate postischemic
cytokine secretion patterns, diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of
neuroinflammation. The aforementioned observations culminated in a first clinical trial, which revealed an improved motor recovery in patients with cortical
stroke after
lithium treatment. Beside its well-known psychiatric indications,
lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases. A detailed understanding of the
lithium-induced mechanisms, however, is important for prospective clinical trials which may pave the way for a successful bench-to-bedside translation in the future. In this review, we will give an overview of
lithium-induced neuroprotective mechanisms under various pathological conditions, with special emphasis on
ischemic stroke.