Enhanced Lithium-Induced Brain Recovery Following Cranial Irradiation Is Not Impeded by Inflammation

Abstract

Radiation-induced brain injury occurs in many patients receiving cranial radiation therapy, and these deleterious effects are most profound in younger patients. Impaired neurocognitive functions in both humans and rodents are associated with inflammation, demyelination, and neural stem cell dysfunction. Here we evaluated the utility of lithium and a synthetic retinoid receptor agonist in reducing damage in a model of brain-focused irradiation in juvenile mice. We found that lithium stimulated brain progenitor cell proliferation and differentiation following cranial irradiation while also preventing oligodendrocyte loss in the dentate gyrus of juvenile mice. In response to inflammation induced by radiation, which may have encumbered the optimal reparative action of lithium, we used the anti-inflammatory synthetic retinoid Am80 that is in clinical use in the treatment of acute promyelocytic leukemia. Although Am80 reduced the number of cyclooxygenase-2-positive microglial cells following radiation treatment, it did not enhance lithium-induced neurogenesis recovery, and this alone was not significantly different from the effect of lithium on this proinflammatory response. Similarly, lithium was superior to Am80 in supporting the restoration of new doublecortin-positive neurons following irradiation. These data suggest that lithium is superior in its restorative effects to blocking inflammation alone, at least in the case of Am80. Because lithium has been in routine clinical practice for 60 years, these preclinical studies indicate that this drug might be beneficial in reducing post-therapy late effects in patients receiving cranial radiotherapy and that blocking inflammation in this context may not be as advantageous as previously suggested. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:469 -479

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

“…According to recent findings, lithium positively regulates the neurogenic process and facilitates the reintegration of newly generated neurons after ablation of neurogenesis [26,27,28,29]. Hence, to investigate the level of integration of young adult-born neurons in the DG following juvenile irradiation and their potential recovery upon lithium treatment, we analyzed the DCX-expressing population 4 months after the insult and the therapeutic treatments (fig.…”

“…It is described that lithium, a potent mood stabilizer, administered chronically to adult mice for 4 weeks, had beneficial effects in replenishing adult-born granule cells after irradiation-induced loss of neurogenesis and in rescuing LTP in a Down syndrome mode [26,29]. …”

“…Lithium has been considered a promising candidate in the prevention and recovery after various types of brain injury, including cranial irradiation, and several studies have demonstrated beneficial effects in restoring adult neurogenesis as well as synaptic plasticity in different disease models [26,27,28,29]. Lithium appears to restore cognitive function in adult as well as in young [29] mice following cranial irradiation and is thought to act partially through the inhibition of neural apoptosis [30] as well as by boosting endogenous neurogenesis [31].…”

“…Lithium appears to restore cognitive function in adult as well as in young [29] mice following cranial irradiation and is thought to act partially through the inhibition of neural apoptosis [30] as well as by boosting endogenous neurogenesis [31]. At present, there is little knowledge of irradiation-induced damage to the brain during development, but since the juvenile brain is even more sensitive to ionizing irradiation than the adult brain [2,5,32], it is of great importance to define the mechanisms that lead to cognitive impairment following such treatment and to conceive therapeutic approaches to rescue the young developing brain from cognitive decline.…”

Effects of Radiation Therapy on Neural Stem Cells

“…Lithium was shown to reduce damage and enhance neurogenesis, and has been explored as a pre-treatment option. Pre-irradiation administration of lithium resulted in reduced apoptosis and microglial activation [97,98]. Lithium increases proliferation of hippocampal NSCs and rescues radiation-induced cell cycle arrest in vitro.…”