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.
Highlights
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)
We examined the biomarkers of brain mitochondrial activity (ETC), neurodegeneration (Glial Fibrillary Acidic Protein, Glial fibrillary acidic protein (GFAP)), Tau, Myelin Basic Protein (MBP) and reactive nitrogen species (NitroTyrosine (N-Tyr), and behavioral outcomes in a rat model of Mild TBI (mTBI) with and without pyruvate treatment
The neuroprotective role of sodium pyruvate administration in acute mTBI was examined for the mitochondrial damage, gliotic, degenerative changes, and oxidative stress to compare against neurobehavioral and motor and sensory functional derangement
Summary
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). 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. Neuropathological studies of TBI patients have shown the accumulation of amyloid plaques following a single severe TBI, and Tau pathology after repeated moderate (mTBI), which are indicators of AD development [3, 4] Based on these and other observations, the blast-related moderate to severe TBI may increase the risk of developing dementia and AD later in life [5, 6]. We examined the biomarkers of brain mitochondrial activity (ETC), neurodegeneration (Glial Fibrillary Acidic Protein, GFAP), Tau, Myelin Basic Protein (MBP) and reactive nitrogen species (NitroTyrosine (N-Tyr), and behavioral outcomes in a rat model of mTBI with and without pyruvate treatment
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