Involvement of calpains in adult neurogenesis: implications for stroke

Abstract

Calpains are ubiquitous proteases involved in cell proliferation, adhesion and motility. In the brain, calpains have been associated with neuronal damage in both acute and neurodegenerative disorders, but their physiological function in the nervous system remains elusive. During brain ischemia, there is a large increase in the levels of intracellular calcium, leading to the activation of calpains. Inhibition of these proteases has been shown to reduce neuronal death in a variety of stroke models. On the other hand, after stroke, neural stem cells (NSC) increase their proliferation and newly formed neuroblasts migrate towards the site of injury. However, the process of forming new neurons after injury is not efficient and finding ways to improve it may help with recovery after lesion. Understanding the role of calpains in the process of neurogenesis may therefore open a new window for the treatment of stroke. We investigated the involvement of calpains in NSC proliferation and neuroblast migration in two highly neurogenic regions in the mouse brain, the dentate gyrus (DG) and the subventricular zone (SVZ). We used mice that lack calpastatin, the endogenous calpain inhibitor, and calpains were also modulated directly, using calpeptin, a pharmacological calpain inhibitor. Calpastatin deletion impaired both NSC proliferation and neuroblast migration. Calpain inhibition increased NSC proliferation, migration speed and migration distance in cells from the SVZ. Overall, our work suggests that calpains are important for neurogenesis and encourages further research on their neurogenic role. Prospective therapies targeting calpain activity may improve the formation of new neurons following stroke, in addition to affording neuroprotection.

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia

“…In addition to directly limiting calpain activity, EPO may counteract the detrimental effects of excess calpain activity that limit neurorepair. For example, after stroke in the mature CNS, excess calpain activity hinders neural stem and neuroblast proliferation and migration [59]. EPO signaling promotes multiple stages of neuronal and oligodendroglial development [44, 60], and thus may counterbalance calpain-induced suppression of repair.…”

Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal

“…Although this finding may be not directly applicable to HCN cells due to different cellular origins and expression profiles of calpain family members, it further validates the existence of the differential cellular functions of calpain 1 and 2 in NSCs. Another study by Machado et al [30] investigated the role of calpain in adult neurogenesis, in which the deletion of calpastatin, the endogenous calpain inhibitor, impaired both NSC proliferation and neuroblast migration while calpain inhibition increased NSC proliferation, migration speed, and distance in the neurogenic regions [30].…”

Cannabis: A Treasure Trove or Pandora's Box?

“…Adult neurogenesis and gliogenesis provide the adult brain with constant supply of new cells that migrate toward and integrate themselves in the circuitry where they are needed. This process has major implications in learning and forgetting, mood disorders and stroke repair [917][918][919]. Adult neuronal stem cells also contain CB 1 Rs [920][921][922][923], and cannabimimetics in most cases stimulate the proliferation of neural progenitors in the neurogenic niches [918,920,922,924].…”