Effects of Pyruvate Administration on Mitochondrial Enzymes, Neurological Behaviors, and Neurodegeneration after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is known to increase the susceptibility to various age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although the role of damaged mitochondrial electron transport chain (ETC) in the progression of AD and PD has been identified, its relationship with altered expression of neurodegenerative proteins has not been examined before. This study aimed to investigate 1) how TBI could affect mitochondrial ETC and neurodegeneration in rat brain regions related to behavioral alteration, and 2) if administration of the key mitochondrial substrate pyruvate can improve the outcome of mild TBI (mTBI). In a rat lateral fluid percussion injury model of mTBI, sodium pyruvate in sterile distilled water (1 g/kg body weight) was administered orally daily for 7 days. The protein expression of mitochondrial ETC enzymes, and neurodegeneration proteins in the hippocampus and cerebral cortex and was assessed on Day 7. The hippocampal and cortical expressions of ETC complex I, III, IV, V were significantly and variably impaired following mTBI. Pyruvate treatment altered ETC complex expression, reduced the nitrosyl stress and the MBP expression in the injured brain area, but increased the expression of the glial fibrillary acidic protein (GFAP) and Tau proteins. Pyruvate after mTBI augmented the Rotarod performance but decreased the horizontal and vertical open field locomotion activities and worsened neurobehavioural severity score, indicating a debilitating therapeutic effect on the acute phase of mTBI. These results suggest bidirectional neuroprotective and neurodegenerative modulating effects of pyruvate on TBI-induced alteration in mitochondrial activity and motor behavior. Pyruvate could potentially stimulate the proliferation of astrogliosis, and lactate acidosis, and caution should be exercised when used as a therapy in the acute phase of mTBI. More effective interventions targeted at multiple mechanisms are needed for the prevention and treatment of TBI-induced long-term neurodegeneration.

Fourier Transform Infrared Imaging—A Novel Approach to Monitor Bio Molecular Changes in Subacute Mild Traumatic Brain Injury

“…In the post-mTBI group, the thickness/density of the myelin sheath decreased with MBP broke down. This increases the vulnerability of exposed axons as well as behavioral deficits and functional connectivity tend to decline [15,67]. MBP dysfunction(s) are related with physiological reactions to stress and emotional states, nervousness, and depression in adulthood and every conceivable marker for rationalities in cerebrum injuries are accounted for in other studies [15,43].…”

Animal Models of Epilepsy: A Phenotype-oriented Review

“…Nonetheless, other studies have indicated FPI models as potential candidates for drug-resistant epilepsy models, contributing to preclinical drug development [ 39 ]. Besides, lateral mild FPI model can also be used for new therapy development in neurodegenerative disorders [ 40 ].…”

Advantages of pyruvate-based fluids in preclinical shock resuscitation-A narrative review

“…Mounting in vivo experimental and clinical findings have documented beneficial effects of pyruvate on the protection of multiorgan metabolism and function against various pathogenic attacks (Ariyannur et al, 2021;De Moraes et al, 2022;Yang et al, 2022;Zhou, 2022). Increasing evidence grounded on cytotoxic tests in animal studies and preliminary clinical trials with several hundreds of healthy volunteers and patients subjected to heart failure, cardiomyopathy, chronic liver disease, diabetes, and mitochondropathy, as well as pyruvate loading tests over the past 50 years all endorse that SP products in commercial markets are basically safe, effective, and practical in human illnesses (Mateva et al, 1996;Petkova et al, 2007;Inoue et al, 2016;De Moraes et al, 2022;Yang et al, 2022;Zhou, 2022).…”