Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Improves Cognitive Functions in Mice after Controlled Cortical Impact Injury

Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults and war veterans. Although research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of an effective therapy to halt the pathogenesis of brain injury. Earlier, we reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson’s disease and Alzheimer’s disease. This study was undertaken to examine the therapeutic efficacy of NaB in a controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and to inhibit the expression of inducible nitric oxide synthase (iNOS) in the hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of the lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displaying a substantial reduction in depression-like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.

Armcx1 Alleviates Secondary Brain Injury After Traumatic Brain Injury by Reducing Apoptosis and Axonal Injury in a Mouse Model of Controlled Cortical Impact

Armcx1 is highly expressed in the brain and is located in the mitochondrial outer membrane of neurons, where it mediates mitochondrial transport. Mitochondrial transport promotes the removal of damaged mitochondria and the replenishment of healthy mitochondria, which are essential for neuronal survival after traumatic brain injury (TBI). This study investigated the role of Armcx1 and its underlying regulator(s) in secondary brain injury (SBI) after TBI. An in vivo TBI model was established in C57BL/6 mice via controlled cortical impact (CCI). Adeno-associated viruses with Armcx1 overexpression and knockdown were constructed and administered to mice by stereotactic cortical injection. Exogenous miR-223-3P mimic or inhibitor was transfected into cultured cortical neurons, which were then scratched to simulate TBI in vitro. The Armcx1 protein level was found to be decreased in peri-lesion tissue, particularly in neurons. The overexpression of Armcx1 significantly reduced TBI-induced neurological dysfunction, apoptosis, axonal injury, and mitochondrial dysfunction, while knockdown of Armcx1 had the opposite effect. Armcx1 was a direct target of miR-223-3P. The miR-223-3P mimic significantly reduced the Armcx1 protein level, while the miR-223-3P inhibitor had the opposite effect. Finally, the miR-223-3P inhibitor significantly improved mitochondrial membrane potential and increased the total length of the neurites without affecting branching numbers, while the miR-223-3P mimic had the opposite effect. In summary, our results suggest that the decreased expression of Armcx1 protein in neurons after experimental TBI aggravates secondary brain injury, which may be regulated by miR-223-3P. Therefore, this study provides a potential therapeutic approach for treating TBI.

Traumatic brain injury augurs ill for prolonged deficits in the brain’s structural and functional integrity following controlled cortical impact injury

Previous neuroimaging studies in rodents investigated effects of the controlled cortical impact (CCI) model of traumatic brain injury (TBI) within one-month post-TBI. This study extends this temporal window to monitor the structural–functional alterations from two hours to six months post-injury. Thirty-seven male Sprague–Dawley rats were randomly assigned to TBI and sham groups, which were scanned at two hours, 1, 3, 7, 14, 30, 60 days, and six months following CCI or sham surgery. Structural MRI, diffusion tensor imaging, and resting-state functional magnetic resonance imaging were acquired to assess the dynamic structural, microstructural, and functional connectivity alterations post-TBI. There was a progressive increase in lesion size associated with brain volume loss post-TBI. Furthermore, we observed reduced fractional anisotropy within 24 h and persisted to six months post-TBI, associated with acutely reduced axial diffusivity, and chronic increases in radial diffusivity post-TBI. Moreover, a time-dependent pattern of altered functional connectivity evolved over the six months’ follow-up post-TBI. This study extends the current understanding of the CCI model by confirming the long-term persistence of the altered microstructure and functional connectivity, which may hold a strong translational potential for understanding the long-term sequelae of TBI in humans.

Sex Differences in Mitochondrial Function Following a Controlled Cortical Impact Traumatic Brain Injury in Rodents

Traumatic brain injury (TBI) is a complex disease to study due to the multifactorial injury cascades occurring after the initial blow to the head. One of the most vital players in this secondary injury cascade, and therapeutic target of interest, is the mitochondrion. Mitochondria are important for the generation of cellular energy, regulation of cell death, and modulation of intracellular calcium which leaves these “powerhouses” especially susceptible to damage and dysfunction following traumatic brain injury. Most of the existing studies involving mitochondrial dysfunction after TBI have been performed in male rodent models, leaving a gap in knowledge on these same outcomes in females. This mini-review intends to highlight the available data on mitochondrial dysfunction in male and female rodents after controlled cortical impact (CCI) as a common model of TBI.