Beyond drug discovery: Exploring the physiological and methodological dimensions of zebrafish in diabetes research.

Diabetes mellitus is a chronic disease that is now considered a global epidemic. Chronic diabetes conditions include type 1 and type 2 diabetes, both of which are normally irreversible. As a result of long-term uncontrolled high levels of glucose, diabetes can progress to hyperglycaemic pathologies, such as cardiovascular diseases, retinopathy, nephropathy and neuropathy, among many other complications. The complete mechanism underlying diabetes remains unclear due to its complexity. In this scenario, zebrafish (Danio rerio) have arisen as a versatile and promising animal model due to their good reproducibility, simplicity, and time- and cost-effectiveness. The Zebrafish model allows us to make progress in the investigation and comprehension of the root cause of diabetes, which in turn would aid in the development of pharmacological and surgical approaches for its management. The current review provides valuable reference information on zebrafish models, from the first zebrafish diabetes models using genetic, disease induction and chemical approaches, to the newest ones that further allow for drug screening and testing. This review aims to update our knowledge related to diabetes mellitus by gathering the most authoritative studies on zebrafish as a chemical, dietary and insulin induction, and genetic model for diabetes research.

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson's Disease Risk.

Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson's disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou's impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate-severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DßH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems.

Epilepsy-associated comorbidities among adults: A plausible therapeutic role of gut microbiota.

Epilepsy is a debilitating disorder that affects about 70 million people in the world currently. Most patients with epilepsy (PWE) often reported at least one type of comorbid disorder. These may include neuropsychiatric disorders, cognitive deficits, migraine, cardiovascular dysfunction, systemic autoimmune disorders and others. Current treatment strategies against epilepsy-associated comorbidities have been based on targeting each disorder separately with either anti-seizure medications (ASMs), anti-inflammatories or anti-depressant drugs, which have often given inconsistent and ineffective results. Gut dysbiosis may be a common pathological pathway between epilepsy and its comorbid disorders, and thus may serve as a possible intervention target. Therefore, this narrative review aimed to elucidate the potential pathological and therapeutic role of the gut microbiota in adult epilepsy-associated comorbidities. This review noticed a scarcity in the current literature on studies investigating the direct role of the gut microbiota in relation to epilepsy-associated comorbidities. Nevertheless, gut dysbiosis have been implicated in both epilepsy and its associated comorbidities, with similarities seen in the imbalance of certain gut microbiota phyla (Firmicutes), but differences seen in the mechanism of action. Current gut-related interventions such as probiotics have been consistently reported across studies to provide beneficial effects in correcting gut dysbiosis and improving various disorders, independent of epilepsy. However, whether these beneficial effects may translate towards epilepsy-associated comorbidities have yet to be determined. Thus, future studies determining the therapeutic potential of gut microbiota interventions in PWE with epilepsy-associated comorbidities may effectively improve their quality of life.

Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology.

Epilepsy is a debilitating disorder of uncontrollable recurrent seizures that occurs as a result of imbalances in the brain excitatory and inhibitory neuronal signals, that could stem from a range of functional and structural neuronal impairments. Globally, nearly 70 million people are negatively impacted by epilepsy and its comorbidities. One such comorbidity is the effect epilepsy has on the autonomic nervous system (ANS), which plays a role in the control of blood circulation, respiration and gastrointestinal function. These epilepsy-induced impairments in the circulatory and respiratory systems may contribute toward sudden unexpected death in epilepsy (SUDEP). Although, various hypotheses have been proposed regarding the role of epilepsy on ANS, the linking pathological mechanism still remains unclear. Channelopathies and seizure-induced damages in ANS-control brain structures were some of the causal/pathological candidates of cardiorespiratory comorbidities in epilepsy patients, especially in those who were drug resistant. However, emerging preclinical research suggest that neurotransmitter/receptor dysfunction and synaptic changes in the ANS may also contribute to the epilepsy-related autonomic disorders. Thus, pathological mechanisms of cardiorespiratory dysfunction should be elucidated by considering the modifications in anatomy and physiology of the autonomic system caused by seizures. In this regard, we present a comprehensive review of the current literature, both clinical and preclinical animal studies, on the cardiorespiratory findings in epilepsy and elucidate the possible pathological mechanisms of these findings, in hopes to prevent SUDEP especially in patients who are drug resistant.

Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation.

A history of repeated concussion has been linked to the later development of neurodegeneration, which is associated with the accumulation of hyperphosphorylated tau and the development of behavioral deficits. However, the role that exogenous factors, such as immune activation, may play in the development of neurodegeneration following repeated mild traumatic brain injury (rmTBI) has not yet been explored. To investigate, male Sprague-Dawley rats were administered three mTBIs 5days apart using the diffuse impact-acceleration model to generate ∼100G. Sham animals underwent surgery only. At 1 or 5days following the last injury rats were given the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline. TLR4 activation had differential effects following rmTBI depending on the timing of activation. When given at 1day post-injury, LPS acutely activated microglia, but decreased production of pro-inflammatory cytokines like IL-6. This was associated with a reduction in neuronal injury, both acutely, with a restoration of levels of myelin basic protein (MBP), and chronically, preventing a loss of both MBP and PSD-95. Furthermore, these animals did not develop behavioral deficits with no changes in locomotion, anxiety, depressive-like behavior or cognition at 3months post-injury. Conversely, when LPS was given at 5days post-injury, it was associated acutely with an increase in pro-inflammatory cytokine production, with an exacerbation of neuronal damage and increased levels of aggregated and phosphorylated tau. At 3months post-injury, there was a slight exacerbation of functional deficits, particularly in cognition and depressive-like behavior. This highlights the complexity of the immune response following rmTBI and the need to understand how a history of rmTBI interacts with environmental factors to influence the potential to develop later neurodegeneration.

High Mobility Group Box-1 (HMGB1), a Key Mediator of Cognitive Decline in Neurotrauma with a Potential for Targeted Therapy: A Comprehensive Review.

Neurotrauma plays a significant role in secondary injuries by intensifying the neuroinflammatory response in the brain. High Mobility Group Box-1 (HMGB1) protein is a crucial neuroinflammatory mediator involved in this process. Numerous studies have hypothesized about the underlying pathophysiology of HMGB1 and its role in cognition, but a definitive link has yet to be established. Elevated levels of HMGB1 in the hippocampus and serum have been associated with declines in cognitive performance, particularly in spatial memory and learning. This review also found that inhibiting HMGB1 can improve cognitive deficits following neurotrauma. Interestingly, HMGB1 levels are linked to the modulation of neuroplasticity and may offer neuroprotective effects in the later stages of neurotraumatic events. Consequently, administering HMGB1 during the acute phase may help reduce neuroinflammatory effects that lead to cognitive deficits in the later stages of neurotrauma. However, further research is needed to understand the time-dependent regulation of HMGB1 and the clinical implications of treatments targeting HMGB1 after neurotrauma.

Feasibility of cardiac-based seizure detection and prediction: A systematic review of non-invasive wearable sensor-based studies.

A reliable seizure detection or prediction device can potentially reduce the morbidity and mortality associated with epileptic seizures. Previous findings indicating alterations in cardiac activity during seizures suggest the usefulness of cardiac parameters for seizure detection or prediction. This study aims to examine available studies on seizure detection and prediction based on cardiac parameters using non-invasive wearable devices. The Embase, PubMed, and Scopus databases were used to systematically search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Human studies that evaluated seizure detection or prediction based on cardiac parameters collected using wearable devices were included. The QUADAS-2 tool and proposed standards for validation for seizure detection devices were used for quality assessment. Twenty-four articles were identified and included in the analysis. Twenty studies evaluated seizure detection algorithms, and four studies focused on seizure prediction. Most studies used either a wrist-worn or chest-worn device for data acquisition. Among the seizure detection studies, cardiac parameters utilized for the algorithms mainly included heart rate (HR) (n = 11) or a combination of HR and heart rate variability (HRV) (n = 6). HR-based seizure detection studies collectively reported a sensitivity range of 56%-100% and a false alarm rate (FAR) of 0.02-8/h, with most studies performing retrospective validation of the algorithms. Three of the seizure prediction studies retrospectively validated multimodal algorithms, combining cardiac features with other physiological signals. Only one study prospectively validated their seizure prediction algorithm using HRV extracted from ECG data collected from a custom wearable device. These studies have demonstrated the feasibility of using cardiac parameters for seizure detection and prediction with wearable devices, with varying algorithmic performance. Many studies are in the proof-of-principle stage, and evidence for real-time detection or prediction is currently limited. Future studies should prioritize further refinement of the algorithm performance with prospective validation using large-scale longitudinal data. PLAIN LANGUAGE SUMMARY: This systematic review highlights the potential use of wearable devices, like wristbands, for detecting and predicting seizures via the measurement of heart activity. By reviewing 24 articles, it was found that most studies focused on using heart rate and changes in heart rate for seizure detection. There was a lack of studies looking at seizure prediction. The results were promising but most studies were not conducted in real-time. Therefore, more real-time studies are needed to verify the usage of heart activity-related wearable devices to detect seizures and even predict them, which will be beneficial to people with epilepsy.

An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-ß (Aß) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aß plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aß plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aß accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

Traumatic brain injury-induced peripheral damage: The dynamics of the inflammatory and autophagy pathway from acute to chronic stages.

INTRODUCTION: Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and brings a huge burden on the quality of life of patients with TBI and the country's healthcare system. Peripheral organs, especially the kidney, and liver, may be affected by the onset of molecular responses following brain tissue damage. While secondary injury responses post TBI has been well studied in the brain, the effect/consequences of these responses in the peripheral organs have not yet been fully elucidated. Thus, our study aimed to investigate the immunoreactivity of these responses, particularly via proinflammatory cytokines and autophagy markers in the kidney and liver post-acute and chronic TBI. MATERIAL AND METHODS: Mild TBI (mTBI) and repetitive mTBI (r-mTBI) were induced in male and female 2-month-old Balb/c mice via the Marmarou weight-drop model. Liver and kidney tissues were sampled at 24 hours (acute) and 30 days (chronic) post TBI and subjected to histopathological and immunoreactivity analysis. RESULTS: Interleukin (IL)-6 levels were significantly increased in the male liver and kidney tissues in both TBI groups compared to the control group but were seen to be decreased in the female r-mTBI chronic liver and r-mTBI acute kidney. Tumor necrosis factor a (TNF-a) levels were found to increase only in the female r-mTBI chronic kidney tissue and mTBI chronic liver tissue. IL-1b levels were increased in the male and female r-mTBI liver tissues but decreased in the female mTBI kidney tissue. Inducible nitric oxide synthase (iNOS) levels were found to be significantly increased in the female mTBI acute and r-mTBI chronic kidney tissue and mTBI liver tissue, but decreased in the r-mTBI acute kidney and r-mTBI liver tissues. Beclin-1 levels were increased in male mTBI chronic and r-mTBI acute liver tissue but decreased in the r-mTBI chronic group. LC3A/B and P62/SQSTM1 levels were significantly increased in the female mTBI chronic and male r-mTBI chronic liver tissues but decreased in the male r-mTBI and female r-mTBI acute kidney tissues. Significant histopathological changes were also observed in the liver and kidney tissue which were dependent on the TBI severity, gender, and time post TBI. CONCLUSIONS: The results showed that TBI may elicit peripheral molecular responses, particularly in terms of alteration in the levels of inflammatory cytokines and autophagy markers, which were gender- and time-dependent. This suggests that TBI may have a significant role in the cellular damage of the kidney and liver in both the acute and chronic phases post TBI, thus ensuring that the effects of TBI may not be confined to the brain.

Elucidating the visual phenomena in epilepsy: A mini review.

Epilepsy is one of the most recognizable neurological diseases, globally. Epilepsy may be accompanied by various complications, including vision impairments, which may severely impact one's quality of life. These visual phenomena may occur in the preictal, ictal and/or postictal periods of seizures. Examples of epilepsy associated visual phenomena include visual aura, visual hallucinations, transient visual loss and amaurosis (blindness). These ophthalmologic signs/symptoms of epilepsy may be temporary or permanent and may vary depending of the type of epilepsy and location of the seizure foci (occipital or temporal lobe). Some visual phenomena may even be utilized to diagnose the epilepsy type, although solely depending on visual symptoms for diagnosis may lead to mistreatment. Some antiseizure medications (ASMs) may also contribute to certain visual disturbances, thereby impacting its therapeutic efficiency for patients with epilepsy (PWE). Although the development of visual comorbidities has been observed diversely among PWE, there may still be a lack of understanding on their relevance and manifestation in epilepsy, which may contribute to the rate of misdiagnosis and the current scarcity in therapeutic relieve. Therefore, this mini narrative review aimed to discuss the common epilepsy associated visual phenomena, based on the available literature. This review also showcased the relationship between the type of visual complications and the site of seizure onset, as well as compared the visual phenomena between occipital lobe epilepsy and temporal lobe epilepsy. Evaluation of these findings may be crucial in reducing the risk of permanent seizure/epilepsy related vision deficits among PWE.

Initial Severity of Injury Has Little Effect on the Temporal Profile of Long-Term Deficits in Locomotion, Anxiety, and Cognitive Function After Diffuse Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with persistent impairments in multiple domains, including cognitive and neuropsychiatric function. Previous literature has suggested that the risk of such impairments may differ as a function of the initial severity of injury, with moderate-severe TBI (msTBI) associated with more severe cognitive dysfunction and mild TBI (mTBI) associated with a higher risk of developing an anxiety disorder. Despite this, relatively few pre-clinical studies have investigated the time course of behavioral change after different severities of injury. The current study compared the temporal profile of functional deficits incorporating locomotion, cognition, and anxiety up to 12 months post-injury after an mTBI, repeated mild TBI (rmTBI), and single msTBI in an experimental model of diffuse TBI. Injury appeared to alter the effect of aging on locomotor activity, with both msTBI and rmTBI rats showing a decrease in locomotion at 12 months relative to their earlier performance on the task, an effect not observed in shams or after a single mTBI. Further, mTBI seemed to be associated with decreased anxiety over time, as measured by increased time spent in the open arm of the elevated plus maze from 3 to 12 months post-injury. No significant findings were observed on spatial memory or volumetric magnetic resonance imaging. Future studies will need to use a more comprehensive behavioral battery, capable of capturing subtle alterations in function, and longer time points, following rats into old age, in order to more fully assess the evolution of persistent behavioral deficits in key domains after different severities of TBI, as well as their accompanying neuroimaging changes. Given the prevalence and significance of such deficits post-TBI for a person's quality of life, as well as the elevated risk of neurodegenerative disease post-injury, such investigations may play a critical role in identifying optimal windows of therapeutic intervention post-injury.

Neuroinflammation: A Common Pathway in Alzheimer's Disease and Epilepsy.

BACKGROUND: Neuroinflammation is an innate immunological response of the central nervous system that may be induced by a brain insult and chronic neurodegenerative conditions. Recent research has shown that neuroinflammation may contribute to the initiation of Alzheimer's disease (AD) pathogenesis and associated epileptogenesis. OBJECTIVE: This systematic review aimed to investigate the available literature on the shared molecular mechanisms of neuroinflammation in AD and epilepsy. METHODS: The search included in this systematic review was obtained from 5 established databases. A total of 2,760 articles were screened according to inclusion criteria. Articles related to the modulation of the inflammatory biomarkers commonly associated with the progression of AD and epilepsy in all populations were included in this review. RESULTS: Only 7 articles met these criteria and were chosen for further analysis. Selected studies include both in vitro and in vivo research conducted on rodents. Several neuroinflammatory biomarkers were reported to be involved in the cross-talk between AD and epilepsy. CONCLUSION: Neuroinflammation was directly associated with the advancement of AD and epilepsy in populations compared to those with either AD or epilepsy. However, more studies focusing on common inflammatory biomarkers are required to develop standardized monitoring guidelines to prevent the manifestation of epilepsy and delay the progression of AD in patients.

The Role of Interferon-α in Neurodegenerative Diseases: A Systematic Review.

BACKGROUND: Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs. OBJECTIVE: This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-α in neurodegeneration/NDs. METHODS: Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search. RESULTS: A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production. CONCLUSION: The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α. Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated.

Neuroprotective potency of mangiferin against 3-nitropropionic acid induced Huntington's disease-like symptoms in rats: possible antioxidant and anti-inflammatory mechanisms.

Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of psychiatric disturbances, cognitive and motor dysfunction. The daily performances and life quality of HD patients have been severely interfered by these clinical signs and symptoms until the last stage of neuronal cell death. To the best of our knowledge, no treatment is available to completely mitigate the progression of HD. Mangiferin, a naturally occurring potent glucoxilxanthone, is mainly isolated from the Mangifera indica plant. Considerable studies have confirmed the medicinal benefits of mangiferin against memory and cognitive impairment in neurodegenerative experimental models such as Alzheimer's and Parkinson's diseases. Therefore, this study aims to evaluate the neuroprotective effect of mangiferin against 3-nitropropionic acid (3-NP) induced HD in rat models. Adult Wistar rats (n = 32) were randomly allocated equally into four groups of eight rats each: normal control (Group I), disease control (Group II) and two treatment groups (Group III and Group IV). Treatment with mangiferin (10 and 20 mg/kg, p. o.) was given for 14 days, whereas 3-NP (15 mg/kg, i. p.) was given for 7 days to induce HD-like symptoms in rats. Rats were assessed for cognitive functions and motor coordination using open field test (OFT), novel object recognition (NOR) test, neurological assessment, rotarod and grip strength tests. Biochemical parameters such as oxidative stress markers and pro-inflammatory markers in brain hippocampus, striatum and cortex regions were evaluated. Histopathological study on brain tissue was also conducted using hematoxylin and eosin (H&E) staining. 3-NP triggered anxiety, decreased recognition memory, reduced locomotor activity, lower neurological scoring, declined rotarod performance and grip strength were alleviated by mangiferin treatment. Further, a significant depletion in brain malondialdehyde (MDA) level, an increase in reduced glutathione (GSH) level, succinate dehydrogenase (SDH), superoxide dismutase (SOD) and catalase (CAT) activities, and a decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6) levels were observed in mangiferin treated groups. Mangiferin also mitigated 3-NP induced histopathological alteration in the brain hippocampus, striatum and cortex sections. It could be inferred that mangiferin protects the brain against oxidative damage and neuroinflammation, notably via antioxidant and anti-inflammatory activities. Mangiferin, which has a good safety profile, may be an alternate treatment option for treating HD and other neurodegenerative disorders. The results of the current research of mangiferin will open up new avenues for the development of safe and effective therapeutic agents in diminishing HD.

Fruits for Seizures? A Systematic Review on the Potential Anti-Convulsant Effects of Fruits and their Phytochemicals.

Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus, alternative methods have been explored to control seizures in these drug-resistant patients. One such method may be through the utilization of fruit phytochemicals. These phytochemicals have been reported to have beneficial properties such as anti-convulsant, anti-oxidant, and anti-inflammatory activities. However, some fruits may also elicit harmful effects. This review aims to summarize and elucidate the anti- or pro-convulsant effects of fruits used in relation to seizures in hopes of providing a good therapeutic reference to epileptic patients and their carers. Three databases, SCOPUS, ScienceDirect, and PubMed, were utilized for the literature search. Based on the PRISMA guidelines, a total of 40 articles were selected for critical appraisal in this review. Overall, the extracts and phytochemicals of fruits managed to effectively reduce seizure activities in various preclinical seizure models, acting mainly through the activation of the inhibitory neurotransmission and blocking the excitatory neurotransmission. Only star fruit has been identified as a pro-convulsant fruit due to its caramboxin and oxalate compounds. Future studies should focus more on utilizing these fruits as possible treatment strategies for epilepsy.

The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review.

BACKGROUND: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses, which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. OBJECTIVE: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. METHODS: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. RESULTS: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington's disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/ diseases. CONCLUSION: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

The Role of Neuroinflammatory Mediators in the Pathogenesis of Traumatic Brain Injury: A Narrative Review.

Traumatic brain injury (TBI) is a debilitating acquired neurological disorder that afflicts nearly 74 million people worldwide annually. TBI has been classified as more than just a single insult because of its associated risk toward various long-term neurological and neurodegenerative disorders. This risk may be triggered by a series of postinjury secondary molecular and cellular pathology, which may be dependent on the severity of the TBI. Among the secondary injury mechanisms, neuroinflammation may be the most crucial as it may exacerbate brain damage and lead to fatal consequences when prolonged. This Review aimed to elucidate the influence of neuroinflammatory mediators on the TBI functional and pathological outcomes, particularly focusing on inflammatory cytokines which were associated with neuronal dysfunctions in the acute and chronic stages of TBI. These cytokines include interleukins (IL) such as IL-1(beta)ß, IL-4, IL-6, IL8, IL-10, IL-18, IL-33 and tumor necrosis factor alpha (TNF-α), which have been extensively studied. Apart from these, IL-2, interferon gamma (IFN-γ), and transforming growth factor-beta (TGF-ß) may also play a significant role in the pathogenesis of TBI. These neuroinflammatory mediators may trigger a series of pathological events such as cell death, microglial suppression, and increased catecholaminergic activity. Interestingly, in the acute phase of TBI, most of these mediators may also play a neuroprotective role by displaying anti-inflammatory properties, which may convert to a pro-inflammatory action in the chronic stages post TBI. Early identification and treatment of these mediators may help the development of more effective treatment options for TBI.

Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk.

The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a target of treatment, and how various dietary interventions may modulate gut microbiota differently have been an area of focus in research. The role of ketogenic diet (KD) in particular has been well-established in other diseases like intractable epilepsy due to its postulated effects on gut microbiome modulation, resulting in neuronal stability and prevention of epileptogenesis. Therefore, this systematic review aimed to critically evaluate the current available literature investigating the interplay between the three distinct entities: ketogenic diet, neurodegeneration, and gut microbiota, which may serve as a focus guide for future neurodegenerative diseases (ND) therapeutic research. A comprehensive literature search was performed on three databases; PubMed, Scopus, and Ovid Medline. A total of 12 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that the hopes of KD as a treatment modality for ND are being ventured into as these individuals are said to acquire gut dysbiosis, primarily through increased colonization of phyla Proteobacteria and Firmicutes. Although positive effects including restoration of healthy gut microbes such as Akkermansia Muciphilia sp., improvement in cognitive functioning and decline in neuro-inflammatory markers were noted, this systematic review also depicted conflicting results such as decrease in alpha and beta species diversity as well as diminution of healthy gut commensals such as Bifidobacteriace. In addition, positive neuromodulation were also observed, notably an increase in cerebral blood perfusion to ventromedial hippocampal region via increased expression of eNOS and clearance of amyloid-beta proteins across the blood-brain-barrier via expression of p-glycoprotein. Neuroprotective mechanisms of ketogenic diet also included downregulation of mTOR expression, to prevention acceleration of pathological diseases such as Alzheimer's. Thus due to this conflicting/contrasting results demonstrated by ketogenic diet, such as a decline in gut species richness, diminution in beneficial microbes and decline cognition unless delivered in an intermittent fasting pattern, further studies may still be required before prior recommendation of a ketogenic diet therapeutic regime in ND patients.

Medical Technology: A Systematic Review on Medical Devices Utilized for Epilepsy Prediction and Management.

BACKGROUND: Epilepsy is a devastating neurological disorder that affects nearly 70 million people worldwide. Epilepsy causes uncontrollable, unprovoked and unpredictable seizures that reduce the quality of life of those afflicted, with 1-9 epileptic patient deaths per 1000 patients occurring annually due to sudden unexpected death in epilepsy (SUDEP). Predicting the onset of seizures and managing them may help patients from harming themselves and may improve their well-being. For a long time, electroencephalography (EEG) devices have been the mainstay for seizure detection and monitoring. This systematic review aimed to elucidate and critically evaluate the latest advancements in medical devices, besides EEG, that have been proposed for the management and prediction of epileptic seizures. A literature search was performed on three databases, PubMed, Scopus and EMBASE. METHODS: Following title/abstract screening by two independent reviewers, 27 articles were selected for critical analysis in this review. RESULTS: These articles revealed ambulatory, non-invasive and wearable medical devices, such as the in-ear EEG devices; the accelerometer-based devices and the subcutaneous implanted EEG devices might be more acceptable than traditional EEG systems. In addition, extracerebral signalbased devices may be more efficient than EEG-based systems, especially when combined with an intervention trigger. Although further studies may still be required to improve and validate these proposed systems before commercialization, these findings may give hope to epileptic patients, particularly those with refractory epilepsy, to predict and manage their seizures. CONCLUSION: The use of medical devices for epilepsy may improve patients' independence and quality of life and possibly prevent sudden unexpected death in epilepsy (SUDEP).

An Interplay Between Post-Traumatic Epilepsy and Associated Cognitive Decline: A Systematic Review.

Background: Post-traumatic epilepsy (PTE) is a devastating neurological outcome of traumatic brain injury (TBI), which may negatively impact the quality of life of patients with TBI, and may impose a huge socioeconomic burden. This burden may be due to long-term functional outcomes associated with PTE, particularly cognitive dysfunction. To date, the relationship between TBI and PTE remains unclear, with little known about how the effect of their link on cognitive function as well. Objective: Thus, this systematic review aimed at elucidating the relationship between PTE and cognitive impairment in adults after TBI based on available clinical studies, in hopes to aid in the development of therapeutic strategies for PTE. Methods: A systematic literature search was performed using 6 databases; MEDLINE, Embase, CINAHL, Psych INFO, Web of Science, and Cochrane to retrieve relevant clinical studies investigating the link between PTE and cognition in the context of TBI. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of relevant studies. Results: A total of six eligible studies were included for critical appraisal in this review after performing the inclusion and exclusion criteria, which involved 1,100 individuals, from 1996 to 2021. The selected studies were derived from the civilian and military population, with a follow-up period that ranged from 6 months to 35 years. The average quality of the involved studies was moderate (6.6, SD = 1.89). Five out of six studies found poorer cognitive performance in people with PTE, compared with those without PTE. Although the association between PTE and cognitive impairment was insignificant after controlling for specific covariates, there was a statistical trend toward significance. Conclusion: This systematic review suggests that there may be a possible link between PTE and cognitive decline in TBI patients, with the latter being reported to occur up to 35 years post injury. Variations in sample sizes, follow-up periods, and neuropsychological assessment tools may be the limitations affecting the interpretation and significance of this relationship. Therefore, future studies with standard cognitive assessment tools may be warranted to solidify the link between TBI-PTE-cognitive dysfunction, prior to the development of therapeutic strategies.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020221702, prospero identifier: CRD42020221702.