Availability of neuregulin-1beta1 protects neurons in spinal cord injury and against glutamate toxicity through caspase dependent and independent mechanisms

Exp Neurol. 2021 Jul 24:113817. doi: 10.1016/j.expneurol.2021.113817. Online ahead of print.ABSTRACTSpinal cord injury (SCI) causes sensorimotor and autonomic impairment that partly reflects extensive, permanent loss of neurons at the epicenter and penumbra of the injury. Strategies aimed at enhancing neuronal protection are critical to attenuate neurodegeneration and improve neurological recovery after SCI. In rat SCI, we previously uncovered that the tissue levels of neuregulin-1beta 1 (Nrg-1β1) are acutely and persistently downregulated in the injured spinal cord. Nrg-1β1 is well-known for its critical roles in the development, maintenance and physiology of neurons and glia in the developing and adult spinal cord. However, despite this pivotal role, Nrg-1β1 specific effects and mechanisms of action on neuronal injury remain largely unknown in SCI. In the present study, using a clinically-relevant model of compressive/contusive SCI in rats and an in vitro model of glutamate toxicity in primary neurons, we demonstrate Nrg-1β1 provides early neuroprotection through attenuation of reactive oxygen species, lipid peroxidation, necrosis and apoptosis in acute and subacute stages of SCI. Mechanistically, availability of Nrg-1β1 following glutamate challenge protects neurons from caspase-dependent and independent cell death that is mediated by modulation of mitochondria associated apoptotic cascades and MAP kinase and AKT signaling pathways. Altogether, our work provides novel...
Source: Experimental Neurology - Category: Neurology Authors: Source Type: research