Ionic homeostasis in brain conditioning

Most of the current focus on developing neuroprotective therapies is aimed at preventing neuronal death. However, these approaches have not been successful despite many years of clinical trials mainly because the numerous side effects observed in humans and absent in animals used at preclinical level. Recently, the research in this field aims to overcome this problem by developing strategies which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1-3 days. A new promising approach for neuroprotection derives from post-conditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and post-conditioning. Although the mechanisms through which these two endogenous protective strategies exert their effects are not yet fully understood, recent evidence highlights that the maintenance of ionic homeostasis plays a key role in propagating these neuroprotective phenomena. The present article will review the role of protein transporters and ionic channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and post-conditioning in adult brain, with particular regards to the Na(+)/Ca2(+) exchangers (NCX), the plasma membrane Ca2(+)-ATPase (PMCA), the Na(+)/H(+) exchange (NHE), the Na(+)/K(+)/2Cl(-) cotransport (NKCC) and the acid-sensing cation channels (ASIC). Ischemic stroke is the third leading cause of death and disability. Up until now, all clinical trials testing potential stroke neuroprotectants failed. For this reason attention of researchers has been focusing on the identification of brain endogenous neuroprotective mechanisms activated after cerebral ischemia. In this context, ischemic preconditioning and ischemic post-conditioning represent two neuroprotecive strategies to investigate in order to identify new molecular target to reduce the ischemic damage

ROLE OF SODIUM/CALCIUM EXCHANGER IN NEURONAL DISFUNCTIONS FOLLOWING HYPOXIC-ISCHEMIC INJURY IN NEONATAL MICE

Background: Hypoxic-ischemic encephalopathy (HIE) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since (1) transient brain ischemia followed by reoxygenation alters ionic homeostasis in adult brain and the plasma membrane sodium/calcium exchanger (NCX) plays a fundamental role in the maintenance of ionic homeostasis during brain ischemia, we aim to demonstrate the involvement of NCX in the pathophysiology of HIE. Methods: Experimental HIE was induced in postnatal day 7 (P7) mice by unilateral elettrocoagulation of the right common carotid artery and subsequent 60 minutes exposure of animals to 8% O2. Expression profiles of NCX from embryos stage to adulthood was done using HI and naïve hippocampus mice. To assess the effect of NCX pharmacological activation, brain infarct volume was evaluated in propidium iodide stained hippocampus sections, obtained at several time points after the administration of the newly synthesized NCX activator, Neurounina. Moreover, the effect of NCX activation on learning and memory was evaluated in P60 mice. Results: An age-dependent NCX-1 and NCX-3 increased expression was evidenced in immature hippocampus in wild-type untreated animals. By contrast NCX-1 and NCX-3 expression was significantly reduced starting from 7 days until 60 days after the hypoxic-ischemic insult. NCX-2 expression did not show any change in the naïve and HI mice at all considered time intervals. Notably, NCX pharmacological activation by the newly synthesized compound neurounina not only reduced infarct volume but improved also the spatial and object memory 8 weeks after HI induction in P7 mice. These findings suggest that an altered ionic homeostasis mediated by the reduced expression of NCX contributes to long-term cognitive deficits in neonatal mice exposed to HIE

Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia

Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period