Lithium fails to enhance neurogenesis in subventricular zone and dentate subgranular zone after intracerebral hemorrhage in rats

Abstract

Objective: Application of lithium induces neurogenesis in the damaged brain in the global cerebral ischemia rat model. In a previous study of rats subjected to intracerebral hemorrhage (ICH), we have found that lithium treatment improves functional recovery and reduces acute brain swelling. In this follow-up study, we investigate whether the known beneficial effect of lithium on functional recovery after ICH can be explained by neurorestorative effect.

Methods: Intracerebral hemorrhage was induced using infusion of collagenase into the striatum in adult rats. Rats were treated by intraperitoneal injection with lithium chloride (1, 2, or 4 mEq/kg/day) or saline for 2 weeks leading to and 2 weeks following ICH induction. From post-ICH days 4–14, 5-bromo-20-deoxyuridine (BrdU) was administered daily. At 2 weeks post-ICH, immunohistochemical staining was performed for BrdU and doublecortin (Dcx).

Results: The neurological scores for lithium-treated rats improved significantly at 2 weeks post-ICH compared to saline-treated rats. In the subgranular zone (SGZ) and lateral subventricular zone (SVZ), numbers of BrdU-positive cells were not significantly different between the saline-treated and pooled lithium-treated groups. No significant differences in numbers of BrdU-positive cells in the SVZ were detected between the saline-treated and any of the lithium-treated groups. No significant differences in numbers of BrdU-positive cells in the SGZ were detected between the saline-treated and 1 mEq/kg lithium-treated group. Rats treated with ≧ 2 mEq/kg lithium had lower numbers of BrdU-positive cells in the SGZ than did rats treated with saline, although this difference was not statistically significant. Numbers of Dcx-positive cells in the medial striatum were not significantly different between the 1 mEq/kg lithium-treated and saline-treated groups.

Conclusion: The present study shows that lithium does not enhance neurogenesis after ICH in rats, and high dose lithium suppresses neurogenesis in the SGZ. Functional recovery after ICH may be attributable to neuroprotective effect, not neuroregenerative effect of lithium.

Keywords:

• Intracerebral hemorrhage
• Lithium
• Neural stem cell
• Neurogenesis

This study was supported by grants of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020).