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Exp Neurol ; 377: 114795, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38657855

ABSTRACT

Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.


Subject(s)
Antioxidants , Brain Injuries, Traumatic , Endoplasmic Reticulum Stress , Mice, Inbred C57BL , Animals , Male , Mice , Brain Injuries, Traumatic/pathology , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/drug therapy , Female , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/physiology , Phosphorylation/drug effects , Antioxidants/pharmacology , Sex Characteristics , Acetophenones/pharmacology , Acetophenones/therapeutic use , Acetophenones/administration & dosage , Thiourea/analogs & derivatives , Thiourea/pharmacology , Thiourea/therapeutic use , Thiourea/administration & dosage , Serine/metabolism , Hydroquinones/pharmacology , Hydroquinones/administration & dosage , Hydroquinones/therapeutic use , Drug Therapy, Combination , Oxidative Stress/drug effects
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