ORCID Profile
0000-0003-0993-5622
Current Organisation
Monash University Monash eResearch Centre
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Publisher: MDPI AG
Date: 26-03-2021
DOI: 10.3390/LIFE11040276
Abstract: Epilepsy is characterized by an imbalance in neurotransmitter activity an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K+) concentration via K+ ion channels. Seizures may disrupt the regulation of inwardly rectifying K+ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K+ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippoc us and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippoc us, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippoc us and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K+ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.
Publisher: Medknow
Date: 2016
Publisher: Elsevier BV
Date: 02-2023
Publisher: Neurotak Publishing
Date: 05-10-2020
DOI: 10.31117/NEUROSCIRN.V3I4.52
Abstract: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. In 2009, the National Trauma Database Malaysia reported that nearly 80% of traumas in the population were caused by road traffic accidents, with 64% of these cases related to TBI. Despite these concerning reports, TBI reporting systems and research are still limited in Malaysia. Thus, this systematic review aimed to identify and evaluate the available literature on TBI in Malaysia in order to uncover the status of TBI research in Malaysia. A comprehensive literature search was performed on four databases (PubMed, Embase, Medline and Scopus) regarding TBI in Malaysia. Critical evaluation of 60 relevant articles after application of inclusion and exclusion criteria have indicated that TBI research in Malaysia may have significant limitations in representing the actual TBI population and was lacking in basic TBI research. Thus, there is a dire need for government and private institutions to provide support for the advancement of TBI reporting and the progression of basic, clinical and translation TBI research in Malaysia. This will create a deeper understanding of TBI, contributing to global TBI knowledge, and advancing the development of efficient interventions for Malaysians with its population heterogeneity taken into consideration.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.BBR.2017.08.035
Abstract: A small but significant proportion of mild traumatic brain injury (mTBI) sufferers will report persistent symptoms, including depression, anxiety and cognitive deficits, in the months, or even years, following the initial event. This is known as post-concussion syndrome and its pathogenesis is not yet known. This study sought to investigate the role of a peripheral inflammatory insult in the development of ongoing behavioral symptoms following a mTBI. To investigate, male Sprague-Dawley rats were administered a single mTBI using the diffuse impact-acceleration model to generate ∼100G of force. Sham animals underwent surgery only. At 5days following surgery, rats were given either the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline via an intraperitoneal injection. mTBI animals showed an exaggerated response to LPS, with an increase in the expression of pro-inflammatory cytokines within the hippoc us at 24h post-dose, an effect not seen in sham animals. This was associated with the development of persistent behavioral deficits in the mTBI:LPS animals at 3 months post-injury. These behavioral deficits consisted of increased time spent immobile on the forced swim-test, indicative of depressive like behavior, impaired cognitive performance on the Barnes Maze and decreased anxiety on the Elevated Plus Maze. In contrast, animals administered mTBI alone had no deficits. This study provides evidence that a peripheral inflammatory stimulus can facilitate ongoing symptoms following a mTBI. As such this provides a basis for further exploration of exogenous factors which promote immune system activation as potential targets for intervention to allow the resolution of symptoms following a mTBI.
Publisher: Mary Ann Liebert Inc
Date: 03-2017
Abstract: Traumatic brain injury (TBI) is the leading cause of disability and death worldwide, affecting as many as 54,000,000-60,000,000 people annually. TBI is associated with significant impairments in brain function, impacting cognitive, emotional, behavioral, and physical functioning. Although much previous research has focused on the impairment immediately following injury, TBI may have much longer-lasting consequences, including neuropsychiatric disorders and cognitive impairment. TBI, even mild brain injury, has also been recognized as a significant risk factor for the later development of dementia and Alzheimer's disease. Although the link between TBI and dementia is currently unknown, several proposed mechanisms have been put forward, including alterations in glucose metabolism, excitotoxicity, calcium influx, mitochondrial dysfunction, oxidative stress, and neuroinflammation. A treatment for the devastating long-term consequences of TBI is desperately needed. Unfortunately, however, no such treatment is currently available, making this a major area of unmet medical need. Increasing the level of neurotrophic factor expression in key brain areas may be one potential therapeutic strategy. Of the neurotrophic factors, granulocyte-colony stimulating factor (G-CSF) may be particularly effective for preventing the emergence of long-term complications of TBI, including dementia, because of its ability to reduce apoptosis, stimulate neurogenesis, and increase neuroplasticity.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.BBR.2019.111912
Abstract: Increasingly, it is being recognised that traumatic brain injury (TBI) is not just an acute event but instead results in ongoing neuronal injury that may lead to chronic impairments in multiple cognitive domains. Of these, deficits in executive function are one of the more common changes reported following TBI, and are a major predictor of well-being, social function and quality of life in in iduals with a history of TBI. In order to fully understand the relationship between TBI and executive dysfunction, including brain mechanisms that may account for this, experimental models are clearly needed. However, to date, there have been a lack of preclinical studies systematically comparing the effect of injury severity on executive function, particularly at long-term timepoints post-injury. Furthermore, many previous studies have not used behavioural measures that are sensitive to the full range of executive function impairments that may manifest after injury, particularly in models of diffuse axonal injury (Lv et al.). The current study aimed to investigate the temporal profile, up to 12 months post-injury, of the evolution of executive dysfunction following different severities of injury in an experimental model of DAI. In order to do so, we utilised a rodent touchscreen paradigm to administer the 5 Choice- Continuous Performance Task (5C-CPT), an extension of the 5-choice serial reaction time task (5CSRT). Interestingly, there were no differences in learning, motivation, attention, response time or impulsivity at 1 month, 6 months or 12 months post-injury in any of the TBI groups compared to sham, regardless of the initial severity of the injury. Instead, most of the effects on executive function seen at the 12 month timepoint appeared to be a result of ageing, not injury. As even the 12-month timepoint represents middle age in the rat, future studies will be needed to further probe these effects, in order to determine whether DAI may influence the presentation of executive dysfunction in older age.
Publisher: Wiley
Date: 04-02-2021
DOI: 10.1111/CNS.13590
Publisher: Wiley
Date: 09-06-2021
DOI: 10.1002/JNR.24861
Abstract: 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 athological 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.
Publisher: MedCrave Group, LLC
Date: 24-05-2016
Publisher: MedCrave Group Kft.
Date: 16-11-2018
Publisher: American Chemical Society (ACS)
Date: 22-06-2022
DOI: 10.1021/ACSCHEMNEURO.2C00196
Abstract: 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)β, 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-β) 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.
Publisher: American Chemical Society (ACS)
Date: 05-04-2021
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BBI.2017.04.006
Abstract: 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.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.BBR.2018.04.009
Abstract: TBI is a significant risk factor for the development of dementia, with the interaction between structural damage from TBI and neuroinflammation potentially driving this relationship. This study investigated the early chronic post-TBI neuroinflammatory response and its relationship to both neurodegenerative pathology and functional impairment up to 3 months post-injury. Sprague-Dawley rats underwent either sham surgery or the Marmarou model of diffuse moderate-severe TBI. At 1-month and 3-months post-injury, a functional battery encompassing motor function, depressive-like behaviour, anxiety and cognition was performed. Western blot and immunohistochemical analysis assessed a range of inflammatory, neurodegenerative and oxidative stress markers. At both 1 and 3-months post injury, depressive-like behaviour was significantly increased in TBI animals, with TBI animals also exhibiting impaired cognitive flexibility at 3 months, although learning and memory remained intact. This was accompanied by a significant decrease in markers of synaptic integrity and astrocytic and microglia number within the pre-frontal cortex at 1-month post-injury, although this resolved by 3-months post-injury. In contrast, minimal pathology was evident within the hippoc us at 1 month, with only a decrease in neurofilament-light seen at 3 months post-injury. Thus, following a moderate-severe diffuse injury, the pre-frontal cortex is most vulnerable to early neuro-structural changes. While these changes are resolved at 3 months post-injury, future studies should investigate whether they re-emerge or progress to other areas, such as the hippoc us, at later time points, which could predispose in iduals to the development of dementia.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.BBR.2019.02.045
Abstract: Traumatic brain injury (TBI) is a common risk factor for later neurodegeneration, which can manifest as dementia. Despite this, little is known about the time-course of development of functional deficits, particularly cognitive and neuropsychiatric impairments, and whether these differ depending on the nature of the initiating insult. Therefore, this study investigated long term functional impairment at 12 months post-injury following diffuse TBI of different severities. Male Sprague-Dawley rats (420-480 g 10-12 weeks) were either given a sham surgery (n = 14) or subjected to Marmarou's impact acceleration model of diffuse TBI for a single mild TBI (n = 12), repetitive mild TBI (3 mild diffuse injuries at 5 day intervals) (n = 14) or moderate to severe TBI (n = 14). At 12 months after injury, they were tested on a functional battery encompassing motor, neuropsychiatric (anxiety and depressive-like) and cognitive function. Our results showed that moderate to severe TBI animals exhibited significant impairments in cognitive flexibility (p = 0.009) on the Barnes maze when compared to age-matched sham animals. Neither repetitive mild TBI nor single mild TBI animals showed significant functional impairments when compared to shams. Thus, this study provides the first insight into chronic functional impairments associated with different severities of diffuse TBI, with moderate to severe TBI being a higher risk factor for impaired cognitive function at 12 months post-injury. Taken together, this may have implications for risk of dementia development following different severities of injury.
Publisher: American Chemical Society (ACS)
Date: 16-10-2020
Publisher: American Chemical Society (ACS)
Date: 06-2020
No related grants have been discovered for Alina Arulsamy.