NHE1 Protein in Repetitive Mild TBI-Mediated Neuroinflammation and Neurological Function Impairment.
John P BielaninShamseldin Ayman Hassan MetwallyHelena C M OftSatya S ParuchuriLin LinOkan CapukNicholas D PennockShanshan SongDandan SunPublished in: Antioxidants (Basel, Switzerland) (2024)
Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na + /H + exchanger protein (NHE1) expression in GFAP + reactive astrocytes, IBA1 + microglia, and OLIG2 + oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.
Keyphrases
- mild traumatic brain injury
- oxidative stress
- spinal cord injury
- white matter
- cerebral ischemia
- diabetic rats
- reactive oxygen species
- traumatic brain injury
- dna damage
- resting state
- young adults
- high frequency
- subarachnoid hemorrhage
- functional connectivity
- protein protein
- binding protein
- amino acid
- type diabetes
- cognitive impairment
- spinal cord
- cell proliferation
- neuropathic pain
- induced apoptosis
- blood brain barrier
- high glucose
- brain injury
- inflammatory response
- signaling pathway
- optic nerve
- hydrogen peroxide
- genome wide
- dna methylation
- adipose tissue
- endoplasmic reticulum stress
- severe traumatic brain injury