Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

Abstract

The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxicischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72 hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4 ± 14.6 mm 3 in controls (n = 15) to 27.6 ± 6.2 mm 3 in lithium-treated animals (n = 14) 7 weeks after HI (P < 0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1b and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72 hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.

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

“…treated with normal saline (control group) or lithium chloride (Sigma-Aldrich, Germany; subsequently addressed as lithium only). Lithium dosage was chosen according to previous reports 10,12 with small modifications. Thus, a dose of 1 mmol/kg was i.p.…”

“…Whereas one study administered lithium immediately after unilateral global hypoxia-ischemia in neonatal rats, another study evaluated effects of lithium delivery 3 h after transient focal cerebral ischemia in rats. 10,12 Observation periods in these studies were short. In the latter study, effects of lithium were evaluated only over 7 days.…”

“…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).…”

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

“…Galectin‐3 has been reported to be produced by activated microglia/macrophages after HI and to be required for resident microglia activation response to HI (Burguillos et al, 2015; Lalancette‐Hébert et al, 2012; Yan et al, 2009). We have previously shown that galectin‐3‐positive microglia is detectable only in areas with overt brain injury (Li et al, 2011). In the present study, we showed that CCL2 expression in the ipsilateral hippocampus of the P9 pups was higher than that of the 3mo mice after HI, indicating that the inflammatory response was more pronounced in the immature brain.…”

Monocyte and microglial activation in patients with mood-stabilized bipolar disorder

“…For instance, lithium has been shown to inhibit micro glial activation and cytokine/chemokine secretion in rats. 36,37 In addition, mood stabilizers and antidepressants have an anti-inflammatory effect on isolated monocytes. 38,39 In this cross-sectional study, however, we are not able to make causal inferences with respect to pharmacodynamic effects.…”