Review of Lithium Effects on Brain and Blood

Abstract

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3β (GSK3β). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/β-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways

“…13 Further pathways include prevention of excitotoxicity, upregulation of antiapoptotic Bcl-2 and brain-derived-neurotrophic factor (BDNF) as well as induction of prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt, all of which promote neuronal survival. [14][15][16][17][18] Moreover, lithium stimulates endogenous neurogenesis and promotes neuronal differentiation under physiological conditions 12,[19][20][21][22][23] and in models of global cerebral ischemia. 12,21 Neuronal differentiation is critically controlled by the RE1-silencing transcription factor (REST, also known as NRSF).…”

Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial

“…Lithium acts by inhibiting glycogen synthetase kinase 3-beta (GSK3B), 33 which in turn inhibits nuclear factors that upregulate growth and survival genes in cells, 34 including the nuclear factor of activated T cells (NFAT) and Wnt. 35 Is GSK3b inhibition associated with relief of neuropathic pain?…”

Effects of lithium chloride and methylprednisolone on experimental spinal cord injury

“…The mechanism appears to involve Wnt/β-catenin signaling pathway. LiCl is also described as a potent neuroprotective agent [14]. Dill et al [15] reported that the administration of GSK-3β inhibitors may facilitate the development of an effective treatment to white matter injuries including spinal cord trauma given the wide use of lithium in humans and that the inactivation of GSK-3β promotes axonal growth and recovery in central nervous system.…”

“…Young [14] reported that chronic administration of LiCl increased the levels of neurotropic factors in the brain. LiCl stimulates not only regeneration but also neurogenesis both in-vitro and in-vivo.…”