Non-pharmacological interventions for traumatic brain injury.

Heterogeneity and variability of symptoms due to the type, site, age, sex, and severity of injury make each case of traumatic brain injury (TBI) unique. Considering this, a universal treatment strategy may not be fruitful in managing outcomes after TBI. Most of the pharmacological therapies for TBI aim at modifying a particular pathway or molecular process in the sequelae of secondary injury rather than a holistic approach. On the other hand, non-pharmacological interventions such as hypothermia, hyperbaric oxygen, preconditioning with dietary adaptations, exercise, environmental enrichment, deep brain stimulation, decompressive craniectomy, probiotic use, gene therapy, music therapy, and stem cell therapy can promote healing by modulating multiple neuroprotective mechanisms. In this review, we discussed the major non-pharmacological interventions that are being tested in animal models of TBI as well as in clinical trials. We evaluated the functional outcomes of various interventions with an emphasis on the links between molecular mechanisms and outcomes after TBI.

High-Dose Vitamin C Prevents Secondary Brain Damage After Stroke via Epigenetic Reprogramming of Neuroprotective Genes.

Vitamin C has recently been identified as an epigenetic regulator by activating ten-eleven translocases (TETs), enzymes involved in generating DNA hydroxymethylcytosine (5hmC). Currently, we investigated whether high-dose vitamin C promotes neuroprotection through epigenetic modulation of 5hmC, if there are sex-specific differences in outcome, and the therapeutic potential of vitamin C in stroke-related comorbidities in adult mice. Post-stroke treatment with ascorbate (reduced form), but not dehydroascorbate (oxidized form), increased TET3 activity and 5hmC levels and reduced infarct following focal ischemia. Hydroxymethylation DNA immunoprecipitation sequencing showed that ascorbate increased 5hmC across the genome and specifically in promoters of several stroke pathophysiology-related genes, particularly anti-inflammatory genes. Ascorbate also decreased markers of oxidative stress, mitochondrial fragmentation, and apoptosis in cortical peri-infarct neurons and promoted motor and cognitive functional recovery in both sexes via TET3. Furthermore, post-stroke ascorbate treatment reduced infarct volume and improved motor function recovery in aged, hypertensive and diabetic male and female mice. Delayed ascorbate treatment at 6 h of reperfusion was still effective at reducing infarct volume and motor impairments in adult mice. Collectively, this study shows that post-stroke treatment with high-dose ascorbate protects the brain through epigenetic reprogramming and may function as a robust therapeutic against stroke injury.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.

Therapeutic potential of nutraceuticals to protect brain after stroke.

Stroke leads to significant neuronal death and long-term neurological disability due to synergistic pathogenic mechanisms. Stroke induces a change in eating habits and in many cases, leads to undernutrition that aggravates the post-stroke pathology. Proper nutritional regimen remains a major strategy to control the modifiable risk factors for cardiovascular and cerebrovascular diseases including stroke. Studies indicate that nutraceuticals (isolated and concentrated form of high-potency natural bioactive substances present in dietary nutritional components) can act as prophylactic as well as adjuvant therapeutic agents to prevent stroke risk, to promote ischemic tolerance and to reduce post-stroke consequences. Nutraceuticals are also thought to regulate blood pressure, delay neurodegeneration and improve overall vascular health. Nutraceuticals potentially mediate these effects by their powerful antioxidant and anti-inflammatory properties. This review discusses the studies that have highlighted the translational potential of nutraceuticals as stroke therapies.

Gene expression changes in thalamus and inferior colliculus associated with inflammation, cellular stress, metabolism and structural damage in thiamine deficiency.

Identification of gene expression changes that promote focal neuronal death and neurological dysfunction can further our understanding of the pathophysiology of these disease states and could lead to new pharmacological and molecular therapies. Impairment of oxidative metabolism is a pathogenetic mechanism underlying neuronal death in many chronic neurodegenerative diseases as well as in Wernicke's encephalopathy (WE), a disorder induced by thiamine deficiency (TD). To identify functional pathways that lead to neuronal damage in this disorder, we have examined gene expression changes in the vulnerable thalamus and inferior colliculus of TD rats using Affymetrix Rat Genome GeneChip analysis in combination with gene ontology and functional categorization assessment utilizing the NetAffx GO Mining Tool. Of the 15 927 transcripts analysed, 125 in thalamus and 141 in inferior colliculus were more abundantly expressed in TD rats compared with control animals. In both regions, the major functional categories of transcripts that were increased in abundance after TD were those associated with inflammation (approximately 33%), stress (approximately 20%), cell death and repair ( approximately 26%), and metabolic perturbation (approximately 19%), together constituting approximately 98% of all transcripts up-regulated. These changes occurred against a background of neuronal cell loss and reactive astro- and microgliosis in both structures. Our results indicate that (i) TD produces changes in gene expression that are consistent with the observed dysfunction and pathology, and (ii) similar alterations in expression occur in thalamus and inferior colliculus, brain regions previously considered to differ in pathology. These findings provide important new insight into processes responsible for lesion development in TD, and possibly WE.