Shih-Jen Tsai

Is mania caused by overactivity of central brain-derived neurotrophic factor?

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems, as well as the intracellular signal-transduction pathway. Recent studies had demonstrated that BDNF may play a role in the antidepressant mechanism and the pathogenesis of major depression. These findings implicated that BDNF may involve in mood regulation. In addition, (1). studies found positive association between BDNF genetic polymorphism and bipolar affective disorders; (2). agents which potentially induce manic states also increase BDNF, and (3). increase in mossy fibers were noted for bipolar affective disorder brain and BDNF is related to the induction of aberrant mossy fiber sprouting. From these finding, it is proposed that BDNF overactivity may be implicated in the manic state. The notion of BDNF overactivity in mania suggests that factors associated with increased BDNF activity may proffer the etiological fundamentals for bipolar affective disorder. Further, exploration of this hypothesis can provide a new direction in the treatment of the bipolar affective disorder.

Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression

Major depressive disorder (MDD) is a common mental disease with unknown etiology. Recent studies have suggested that decreased brain-derived neurotrophic factor (BDNF) may be implicated in the pathogenesis of MDD. Instead of a decrease in central BDNF, however, studies utilizing genetic depression animal models have found elevated levels of the factor. In the brain, BDNF exerts its influence chiefly by signaling through tyrosine receptor kinase B (Trk-B). In this report, it is suggested that Trk-B pathway down-regulation may be the major pathogenesis for MDD, while stress, which may reduce central BDNF, acts as a precipitation factor to further dampen central BDNF activity and contribute to the development of depression. Further, several possible mechanisms of Trk-B pathway down-regulation, and the implications for this down-regulation in MDD are discussed.

Lithium may be useful in the prevention of Alzheimer’s disease in individuals at risk of presenile familial Alzheimer’s disease

Alzheimers disease (AD) is the most common form of dementia among older people. Presenile familial AD (FAD) and sporadic Alzheimers disease (SAD) have identical brain lesions, containing senile plaques with beta-amyloid (Abeta) peptide and neurofibrillary tangles formed by hyperphosphorylation of a microtubule-associated protein known as tau. However, FAD and SAD differ in onset and genetic transmission. Unlike SAD, presenile FAD is transmitted as a pure autosomal dominant trait. The authors suggest that lithium could be used for AD prevention, particularly in individuals at risk of presenile FAD, which has early onset. Evidence supporting this hypothesis suggests that lithium decreases Abeta peptide production and inhibits the activity of glycogen synthase kinase-3 which induces aggregation of tau protein into tangles, and tau hyperphosphorylation. Prevalence of AD is lower in patients with chronic lithium treatment, which also increases brain-derived neurotrophic factor activity, so might prevent onset in patients at risk for AD. Several considerations are suggested for prevention trials: the effect of lithium could be evaluated in young animal models that express presenile FAD mutant genes; the time, dose, duration and monitoring of lithium therapy are considered; early phenotypes could be monitored for treatment effect; and some other agents, like valproic acid, could also be candidates for prevention.