Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells

Abstract

Neurogenesis in the adult dentate gyrus (DG) is considered to be partly involved in the action of mood stabilizers. However, it remains unclear how mood stabilizers affect neural precursor cells in adult DG. We have established a culture system of adult rat DG-derived neural precursor cells (ADP) and have shown that lithium, a mood stabilizer, and dexamethasone, an agonist of glucocorticoid receptor, reciprocally regulate ADP proliferation. Neurogenesis constitutes not only proliferation of neural precursor cells but also apoptosis and differentiation. To develop further understanding of mood stabilizer effects on neural precursor cells in adult DG, we investigated and compared the effects of four common mood stabilizers--lithium, valproate, carbamazepine, and lamotrigine--on ADP proliferation, apoptosis, and differentiation. ADP proliferation, decreased by dexamethasone, was examined using Alamar Blue assay. Using TUNEL assay, ADP apoptosis induced by staurosporine was examined. The differentiated ADP induced by retinoic acid was characterized by immunostaining with anti-GFAP or anti-Tuj1 antibody. Lithium and valproate, but not carbamazepine and lamotrigine, recovered ADP proliferation decreased by dexamethasone. All four mood stabilizers decreased ADP apoptosis.Retinoic acid differentiated ADP into both neurons and astrocytes. Lithium and carbamazepine increased the ratio of neurons and decreased that of astrocytes. However, valproate and lamotrigine increased the ratio of astrocytes and decreased that of neurons. Therefore, these four stabilizers exhibited both common and differential effects on ADP proliferation, apoptosis, and differentiation.

Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models

“…In hippocampal neural progenitor/precursor cell cultures, lithium increased proliferation, decreased apoptosis, and selectively 1437 www.chinaphar.com Wang ZF et al Acta Pharmacologica Sinica npg enhanced the neuronal differentiation of these cells [81,82] . Lithium treatment enhanced ERK and CREB phosphorylation in cultured hippocampal neural progenitor cells; PD98059, a MEK inhibitor, significantly decreased lithium-induced neuronal subtype differentiation [82] .…”

GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

“…To estimate the effects of drugs on the number of cells, we used Alamar Blue assay (Invitrogen) as in the cases of our previous studies [7,8]. GDNF and/or stattic.…”

“…GDNF and/or stattic. After 7 days, immunocytochemistry was performed with our previour studies [7,8]. Primary antibodies were used at the following concentrations: mouse anti-nestin anti-phospho-STAT3 (Tyr705) antibody (1:1000; Cell Signaling) as described in our past study (Boku et al, 2009).…”

“…We have previously demonstrated, using a cell culture of the adult rat DG-derived neural precursor cells (ADP) [7], that common mood stabilizers such as lithium, valproate, carbamazepine and lamotrigine promote ADP proliferation, survival and differentiation [8].…”

Anti-Stress Effects of Mood Stabilizers and Relevance to Their Therapeutic Actions

“…Boku et al (2011) demonstrated that lithium and valproate, but not carbamazepine and lamotrigine, prevented the decrease in dentate gyrus-derived neural precursor cell proliferation induced by dexamethasone. However, all four mood stabilizers blocked apoptosis of dentate gyrusderived neural precursor cells.…”