Supplements, nutrition, and alternative therapies for the treatment of traumatic brain injury.

Studies using traditional treatment strategies for mild traumatic brain injury (TBI) have produced limited clinical success. Interest in treatment for mild TBI is at an all time high due to its association with the development of chronic traumatic encephalopathy and other neurodegenerative diseases, yet therapeutic options remain limited. Traditional pharmaceutical interventions have failed to transition to the clinic for the treatment of mild TBI. As such, many pre-clinical studies are now implementing non-pharmaceutical therapies for TBI. These studies have demonstrated promise, particularly those that modulate secondary injury cascades activated after injury. Because no TBI therapy has been discovered for mild injury, researchers now look to pharmaceutical supplementation in an attempt to foster success in human clinical trials. Non-traditional therapies, such as acupuncture and even music therapy are being considered to combat the neuropsychiatric symptoms of TBI. In this review, we highlight alternative approaches that have been studied in clinical and pre-clinical studies of TBI, and other related forms of neural injury. The purpose of this review is to stimulate further investigation into novel and innovative approaches that can be used to treat the mechanisms and symptoms of mild TBI.

The neuroprotective potential of phytochemicals in traumatic brain injury: mechanistic insights and pharmacological implications.

Traumatic brain injury (TBI) leads to brain damage, comprising both immediate primary damage and a subsequent cascade of secondary injury mechanisms. The primary injury results in localized brain damage, while the secondary damage initiates inflammatory responses, followed by the disruption of the blood-brain barrier, infiltration of peripheral blood cells, brain edema, and the release of various immune mediators, including chemotactic factors and interleukins. TBI disrupts molecular signaling, cell structures, and functions. In addition to physical tissue damage, such as axonal injuries, contusions, and haemorrhages, TBI interferes with brain functioning, impacting cognition, decision-making, memory, attention, and speech capabilities. Despite a deep understanding of the pathophysiology of TBI, an intensive effort to evaluate the underlying mechanisms with effective therapeutic interventions is imperative to manage the repercussions of TBI. Studies have commenced to explore the potential of employing natural compounds as therapeutic interventions for TBI. These compounds are characterized by their low toxicity and limited interactions with conventional drugs. Moreover, many natural compounds demonstrate the capacity to target various aspects of the secondary injury process. While our understanding of the pathophysiology of TBI, there is an urgent need for effective therapeutic interventions to mitigate its consequences. Here, we aimed to summarize the mechanism of action and the role of phytochemicals against TBI progression. This review discusses the therapeutic implications of various phytonutrients and addresses primary and secondary consequences of TBI. In addition, we highlighted the roles of emerging phytochemicals as promising candidates for therapeutic intervention of TBI. The review highlights the neuroprotective roles of phytochemicals against TBI and the mechanistic approach. Furthermore, our efforts focused on the underlying mechanisms, providing a better understanding of the therapeutic potential of phytochemicals in TBI therapeutics.

Role of Tau Acetylation in Alzheimer's Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment.

Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.

Temporal profile of M1 and M2 responses in the hippocampus following early 24h of neurotrauma.

Traumatic brain injury (TBI) elicits complex inflammatory assets (M1 and M2 responses) in the brain that include the expression of various cytokines/chemokines and the recruitment of blood cells, contributing secondary injury cascades (SIC), and also recovery processes. The modulation of such inflammatory assets might be a therapeutic option following TBI. The present study assesses a temporal profile of various molecular markers of M1 and M2 response in the hippocampus after TBI. Following a unilateral controlled cortical impact (CCI) on young rats, hippocampal tissues of each brain were harvested at 2, 4, 6, 10, and 24h post trauma. Including shams (craniotomy only), half of the rats were assessed for gene expression and half for the protein of various markers for M1 [interferon-gamma (IFNγ), tumor necrosis factor-α (TNFα), interleukin (IL)-1-ß (IL-1ß), and IL-6] and M2 [IL-4, IL-10, IL-13, arginase 1 (Arg1), YM1, FIZZ1, and mannose receptor C-1 (MRC1)] responses. Analysis revealed that molecular markers of M1 and M2 responses have heterogeneous injury effects in the hippocampus and that "time-post-injury" is an important factor in determining inflammation status. With the heterogeneous gene expression of pro-inflammatory cytokines, M1 response was significantly elevated at 2h and declined at 24h after TBI, however, their levels remained higher than the sham rats. Except IFNγ, proteins of M1 cytokines were significantly elevated in the first 24h, and peaked between 2-6h [TNFα (2h), IL-1ß (6h), and IL-6 (4-6h)]. With the heterogeneous relative gene expression of Arg1, YM1, FIZZ1, and MRC1, levels of M2 cytokines were peaked at 24h post TBI. IL-10 and IL-13 expression appeared biphasic in the first 24h. Protein values of IL-4 and IL-13 peaked at 24h and IL-10 at 6h post injury. Results suggest that the M1 response rises rapidly after injury and overpowers the initial, comparatively smaller, or transient M2 response. A treatment that can modulate inflammation, reduce SIC, and improve recovery should be initiated early (within 10h) after TBI.

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma.

Nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase; NOX) is a complex enzyme responsible for increased levels of reactive oxygen species (ROS), superoxide (O2(•-)). NOX-derived O2(•-) is a key player in oxidative stress and inflammation-mediated multiple secondary injury cascades (SIC) following traumatic brain injury (TBI). The O2(•-) reacts with nitric oxide (NO), produces various reactive nitrogen species (RNS), and contributes to apoptotic cell death. Following a unilateral cortical contusion, young adult rats were killed at various times postinjury (1, 3, 6, 12, 24, 48, 72, and 96 h). Fresh tissue from the hippocampus was analyzed for NOX activity, and level of O2(•-). In addition we evaluated the translocation of cytosolic NOX proteins (p67(Phox), p47(Phox), and p40(Phox)) to the membrane, along with total NO and the activation (phosphorylation) of endothelial nitric oxide synthase (p-eNOS). Results show that both enzymes and levels of O2(•-) and NO have time-dependent injury effects in the hippocampus. Translocation of cytosolic NOX proteins into membrane, NOX activity, and O2(•-) were also increased in a time-dependent fashion. Both NOX activity and O2(•-) were increased at 6 h. Levels of p-eNOS increased within 1h, with significant elevation of NO at 12h post-TBI. Levels of NO failed to show a significant association with p-eNOS, but did associate with O2(•-). NOX up-regulation strongly associated with both the levels of O2(•-) and the total NO. The initial 12 h post-TBI are very important as a possible window of opportunity to interrupt SIC. It may be important to selectively target the translocation of cytosolic subunits for the modulation of NOX function.