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  1. Fulltext Malaysian society of neurosciences (MSN) –Asian and Oceanian myology centre (AOMC) annual scientific meeting 2018
    Lim, Kheng-Seang, Goh, Khean-Jin, Tan, Ai-Huey, Low, Soon-Chai, Mustapha Muzaimi
    Neuroscience Research Notes, 2018;1(2):6-11.
    MyJurnal
    The conjoint 17thAsian and Oceanian Myology Centre (AOMC) and 28thMalaysian Society of Neurosciences (MSN) Annual Scientific Meeting, held in Hotel Istana, Kuala Lumpur, Malaysia from 27 to 29 July 2018, was a great success to gather all neurosciences professionals locally and in the Asian-Oceanian region to share the latest updates in Neurology and specifically Myology. This congress attracted 516 local participants and 167 international delegates from 14 countries
  2. Fulltext Microgravity environment and compensatory: Decompensatory phases for intracranial hypertension form new perspectives to explain mechanism underlying communicating hydrocephalus and its related disorders
    Idris Z, Mustapha M, Abdullah JM
    Asian J Neurosurg, 2014 Jan;9(1):7-13.
    PMID: 24891884 DOI: 10.4103/1793-5482.131058
    The pathogenesis underlying communicating hydrocephalus has been centered on impaired cerebrospinal fluid (CSF) outflow secondary to abnormal CSF pulsation and venous hypertension. Hydrodynamic theory of hydrocephalus fares better than traditional theory in explaining the possible mechanisms underlying communicating hydrocephalus. Nonetheless, hydrodynamic theory alone could not fully explain some conditions that have ventriculomegaly but without hydrocephalus. By revisiting brain buoyancy from a fresher perspective, called microgravity environment of the brain, introducing wider concepts of anatomical and physiological compensatory-decompensatory phases for a persistent raise in intracranial pressure, and along with combining these two concepts with the previously well-accepted concepts of Monro-Kellie doctrine, intracranial hypertension, cerebral blood flow, cerebral perfusion pressure, brain compliance and elasticity, cerebral autoregulation, blood-brain and blood-CSF barriers, venous and cardiopulmonary hypertension, Windkessel phenomenon, and cerebral pulsation, we provide plausible explanations to the pathogenesis for communicating hydrocephalus and its related disorders.
  3. Neuropharmacological potentials of β-carboline alkaloids for neuropsychiatric disorders
    Ayipo YO, Mordi MN, Mustapha M, Damodaran T
    Eur J Pharmacol, 2021 Feb 15;893:173837.
    PMID: 33359647 DOI: 10.1016/j.ejphar.2020.173837
    Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. β-Carboline (βC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the βC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that βC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.
  4. Fulltext A Review of Post-Stroke Cognitive Impairment and the Potential Benefits of Stingless Bee Honey Supplementation
    Ja'afar NL, Mustapha M, Mohamed M, Hashim S
    Malays J Med Sci, 2024 Jun;31(3):75-91.
    PMID: 38984252 DOI: 10.21315/mjms2024.31.3.5
    Post-stroke cognitive impairment (PSCI) is a common decline in cognitive abilities that occurs within 3 months after a stroke. During recovery, stroke survivors often experience varying degrees of cognitive decline, with some patients experiencing permanent cognitive deficits. Thus, it is crucial to prioritise recovery and rehabilitation after a stroke to promote optimal protection of and improvement in cognitive function. Honey derived from stingless bees has been linked to various therapeutic properties, including neuroprotective effects. However, scientific evidence for the mechanisms through which these honey supplements enhance cognitive function remains limited. This narrative review aims to provide an overview of the causes of PSCI, current treatments, the biomarkers influencing cognition in post-stroke patients and the potential of stingless bee honey (SBH) as a neuroprotective agent against the progression of PSCI.
  5. Fulltext Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease
    Lee NT, Ong LK, Gyawali P, Nassir CMNCM, Mustapha M, Nandurkar HH, et al.
    Biomolecules, 2021 07 06;11(7).
    PMID: 34356618 DOI: 10.3390/biom11070994
    The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.
  6. Fulltext Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases: a systematic review
    Yap KH, Azmin S, Makpol S, Damanhuri HA, Mustapha M, Hamzah JC, et al.
    Neural Regen Res, 2023 Jun;18(6):1179-1185.
    PMID: 36453391 DOI: 10.4103/1673-5374.360164
    Trehalose, a unique nonreducing crystalline disaccharide, is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging, intrinsic mutations, or autophagy dysregulation. This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders (tau pathology, synucleinopathy, polyglutamine tract, and motor neuron diseases). All animal studies on neurodegenerative diseases treated with trehalose published in Medline (accessed via EBSCOhost) and Scopus were considered. Of the 2259 studies screened, 29 met the eligibility criteria. According to the SYstematic Review Center for Laboratory Animal Experiment (SYRCLE) risk of bias tool, we reported 22 out of 29 studies with a high risk of bias. The present findings support the purported role of trehalose in autophagic flux and protein refolding. This review identified several other lesser-known pathways, including modifying amyloid precursor protein processing, inhibition of reactive gliosis, the integrity of the blood-brain barrier, activation of growth factors, upregulation of the downstream antioxidant signaling pathway, and protection against mitochondrial defects. The absence of adverse events and improvements in the outcome parameters were observed in some studies, which supports the transition to human clinical trials. It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways. However, heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion. Translational studies on trehalose would need to clarify three important questions: 1) bioavailability with oral administration, 2) optimal time window to confer neuroprotective benefits, and 3) optimal dosage to confer neuroprotection.
  7. Fulltext Cerebral Small Vessel Disease (CSVD) - Lessons From the Animal Models
    Mustapha M, Nassir CMNCM, Aminuddin N, Safri AA, Ghazali MM
    Front Physiol, 2019;10:1317.
    PMID: 31708793 DOI: 10.3389/fphys.2019.01317
    Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and imaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. Unlike large vessels, it is a challenge to visualize small vessels in vivo, hence the difficulty to directly monitor the natural progression of the disease. CSVD might progress for many years during the early stage of the disease as it remains asymptomatic. Prevalent among elderly individuals, CSVD has been alarmingly reported as an important precursor of full-blown stroke and vascular dementia. Growing evidence has also shown a significant association between CSVD's radiological manifestation with dementia and Alzheimer's disease (AD) pathology. Although it remains contentious as to whether CSVD is a cause or sequelae of AD, it is not far-fetched to posit that effective therapeutic measures of CSVD would mitigate the overall burden of dementia. Nevertheless, the unifying theory on the pathomechanism of the disease remains elusive, hence the lack of effective therapeutic approaches. Thus, this chapter consolidates the contemporary insights from numerous experimental animal models of CSVD, to date: from the available experimental animal models of CSVD and its translational research value; the pathomechanical aspects of the disease; relevant aspects on systems biology; opportunities for early disease biomarkers; and finally, converging approaches for future therapeutic directions of CSVD.
  8. Fulltext Is cerebral small vessel disease a central nervous system interstitial fluidopathy?
    Abdul Hamid H, Hambali A, Okon U, Che Mohd Nassir CMN, Mehat MZ, Norazit A, et al.
    IBRO Neurosci Rep, 2024 Jun;16:98-105.
    PMID: 39007087 DOI: 10.1016/j.ibneur.2023.12.004
    A typical anatomical congregate and functionally distinct multicellular cerebrovascular dynamic confer diverse blood-brain barrier (BBB) and microstructural permeabilities to conserve the health of brain parenchymal and its microenvironment. This equanimity presupposes the glymphatic system that governs the flow and clearance of metabolic waste and interstitial fluids (ISF) through venous circulation. Following the introduction of glymphatic system concept, various studies have been carried out on cerebrospinal fluid (CSF) and ISF dynamics. These studies reported that the onset of multiple diseases can be attributed to impairment in the glymphatic system, which is newly referred as central nervous system (CNS) interstitial fluidopathy. One such condition includes cerebral small vessel disease (CSVD) with poorly understood pathomechanisms. CSVD is an umbrella term to describe a chronic progressive disorder affecting the brain microvasculature (or microcirculation) involving small penetrating vessels that supply cerebral white and deep gray matter. This review article proposes CSVD as a form of "CNS interstitial fluidopathy". Linking CNS interstitial fluidopathy with CSVD will open a better insight pertaining to the perivascular space fluid dynamics in CSVD pathophysiology. This may lead to the development of treatment and therapeutic strategies to ameliorate the pathology and adverse effect of CSVD.
  9. Fulltext Ratio of Nitric Oxide Metabolite Levels in Cerebrospinal Fluid and Serum, and Their Correlation with Severity and Outcome in Patients with Subarachnoid Haemorrhage
    Kho GS, Kandasamy R, Bujang MA, Swammy M, Mustapha M, Abdullah JM
    Malays J Med Sci, 2021 Dec;28(6):42-54.
    PMID: 35002489 DOI: 10.21315/mjms2021.28.6.5
    BACKGROUND: Nitric oxide (NO) is involved in a multitude of physiological processes in the central nervous system (CNS). Given the ubiquitous nature of NO and its involvement in various vital processes, nitric oxide metabolite (NOx) has been investigated as a biomarker in CNS diseases. This study aims to investigate the ratio of NOx levels and serum in cerebrospinal fluid (CSF) in patients with spontaneous subarachnoid haemorrhage (SAH). The associations among these markers with clinical outcomes were also studied.

    METHODS: A prospective cohort study was conducted over a 2-year period (May 2013-May 2015) to investigate the levels of NOx in the CSF and serum of patients with radiologically confirmed aneurysmal SAH. NOx samples and all relevant data were collected from the patients on admission and serially over 5 days. On admission, NOx levels were compared between the groups of patients, who were divided as per the World Federation Neurosurgeons Score (WFNS) grading scale, Fisher scale, occurrence of vasospasm on transcranial doppler (TCD), and Glasgow outcome scale (GOS) upon discharge and at 6 months follow-up. The ratios of CSF-to-serum were calculated and correlated with SAH severity and the outcome parameters listed above.

    RESULTS: The patients (N = 40) had a mean (SD) age of 58.2 (11.8) years old. The majority (65%) had a higher severity of SAH (WFNS score 3-5). On evaluation of the CT scan findings, 74% had outcomes equivalent to 4 on the Fisher scale. Vasospasm was detected via TCD in nearly half (45%) of the cohort during the study period; 80% were noted to have a poor outcome (GOS 1-3) at discharge; this persisted at 6 months follow-up. Comparison of NOx levels in the CSF/serum ratio was based on the incidence of vasospasm and severity of outcome (GOS) for day-1 and day-4. Statistically significant results were evident for patients with better outcomes, high severity grading, and the presence of vasospasm (P-values: 0.031, 0.034 and 0.043, respectively).

    CONCLUSION: Elevated NOx levels in CSF and serum and reductions in the ratio of NOx in CSF/serum were found to be associated with severity, occurrence of vasospasm and clinical outcome in aneurysmal SAH patients. This indicates the possible role of NOx as a biomarker to assess severity and prognosis in patients with SAH.

  10. Fulltext An overview of fractional anisotropy as a reliable quantitative measurement for the corticospinal tract (CST) integrity in correlation with a Fugl-Meyer assessment in stroke rehabilitation
    Zolkefley MKI, Firwana YMS, Hatta HZM, Rowbin C, Nassir CMNCM, Hanafi MH, et al.
    J Phys Ther Sci, 2021 Jan;33(1):75-83.
    PMID: 33519079 DOI: 10.1589/jpts.33.75
    [Purpose] Understanding the essential mechanisms in post-stroke recovery not only provides important basic insights into brain function and plasticity but can also guide the development of new therapeutic approaches for stroke patients. This review aims to give an overview of how various variables of Magnetic Resonance-Diffusion Tensor Imaging (MR-DTI) metrics of fractional anisotropy (FA) can be used as a reliable quantitative measurement and indicator of corticospinal tract (CST) changes, particularly in relation to functional motor outcome correlation with a Fugl-Meyer assessment in stroke rehabilitation. [Methods] PubMed electronic database was searched for the relevant literature, using key words of diffusion tensor imaging (dti), corticospinal tract, and stroke. [Results] We reviewed the role of FA in monitoring CST remodeling and its role of predicting motor recovery after stroke. We also discussed the mechanism of CST remodeling and its modulation from the value of FA and FMA-UE. [Conclusion] Heterogeneity of post-stroke brain disorganization and motor impairment is a recognized challenge in the development of accurate indicators of CST integrity. DTI-based FA measurements offer a reliable and evidence-based indicator for CST integrity that would aid in predicting motor recovery within the context of stroke rehabilitation.
  11. Fulltext Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism
    Che Mohd Nassir CMN, Damodaran T, Yusof SR, Norazit A, Chilla G, Huen I, et al.
    Pharmaceutics, 2021 Aug 05;13(8).
    PMID: 34452169 DOI: 10.3390/pharmaceutics13081207
    The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood-brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU-a crossroad of the immune-vascular-nervous system-which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.
  12. Fulltext Hypoxia-Induced Neuroinflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Centella asiatica
    Hambali A, Kumar J, Hashim NFM, Maniam S, Mehat MZ, Cheema MS, et al.
    Front Physiol, 2021;12:712317.
    PMID: 34721056 DOI: 10.3389/fphys.2021.712317
    Alzheimer's disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.
  13. Fulltext Polysaccharide-Based Hydrogels for Microencapsulation of Stem Cells in Regenerative Medicine
    Lee SY, Ma J, Khoo TS, Abdullah N, Nik Md Noordin Kahar NNF, Abdul Hamid ZA, et al.
    Front Bioeng Biotechnol, 2021;9:735090.
    PMID: 34733829 DOI: 10.3389/fbioe.2021.735090
    Stem cell-based therapy appears as a promising strategy to induce regeneration of damaged and diseased tissues. However, low survival, poor engraftment and a lack of site-specificity are major drawbacks. Polysaccharide hydrogels can address these issues and offer several advantages as cell delivery vehicles. They have become very popular due to their unique properties such as high-water content, biocompatibility, biodegradability and flexibility. Polysaccharide polymers can be physically or chemically crosslinked to construct biomimetic hydrogels. Their resemblance to living tissues mimics the native three-dimensional extracellular matrix and supports stem cell survival, proliferation and differentiation. Given the intricate nature of communication between hydrogels and stem cells, understanding their interaction is crucial. Cells are incorporated with polysaccharide hydrogels using various microencapsulation techniques, allowing generation of more relevant models and further enhancement of stem cell therapies. This paper provides a comprehensive review of human stem cells and polysaccharide hydrogels most used in regenerative medicine. The recent and advanced stem cell microencapsulation techniques, which include extrusion, emulsion, lithography, microfluidics, superhydrophobic surfaces and bioprinting, are described. This review also discusses current progress in clinical translation of stem-cell encapsulated polysaccharide hydrogels for cell delivery and disease modeling (drug testing and discovery) with focuses on musculoskeletal, nervous, cardiac and cancerous tissues.
  14. Role of toll-like receptor 4 antagonist Lipopolysaccharide-Rhodobacter sphaeroides on acute stress-induced voluntary ethanol preference and drinking behaviour: In vivo Swiss Albino mouse model
    Chuang HG, Aziz NHA, Wong JH, Mustapha M, Abdullah JM, Idris Z, et al.
    Eur Neuropsychopharmacol, 2021 04;45:59-72.
    PMID: 32014377 DOI: 10.1016/j.euroneuro.2019.12.121
    The present study focused on investigating the effect of toll-like receptor 4 (TLR4) antagonist Lipopolysaccharide-Rhodobacter sphaeroides(LPS-RS) on acute, stress-induced voluntary ethanol preference and drinking behaviour, neuronal components activation, and gene expression associated with stress and addictive behaviour. This study involved the exposure of restraint stress and social isolation using Swiss Albino mice. Two-bottle choice ethanol preference analysis was used in the evaluation of voluntary ethanol seeking and drinking behaviour. Several behavioural assessments were carried out to assess fear and anxiety-like behaviour, neuromuscular ability, motor coordination and locomotion. Morphological and immunoreactivity analysis and gene expression analysis were done after the completion of behavioural assessments. TLR4 antagonist LPS-RS treated stressed-mice showed a significant decrease in ethanol drinking compared with stressed mice. Behavioural results showed that stress exposure induced fear and anxiety-like behaviour; however; no significant deficit was found on motor coordination, neuromuscular ability, locomotion and exploratory behaviour among groups. Morphological analysis showed no significant change in the prefrontal cortex and hippocampus among all groups, while immunoreactivity analysis showed higher expression of c-Fos in prefrontal cortex and hippocampus, higher TLR4 expression in the prefrontal cortex and glial fibrillary acidic protein (GFAP) in hippocampus among stressed-animals. Stressed-mice also showed significant increase in TLR4, Nuclear Factor-Kappa B (NF-kB), inducible nitric oxide synthase (iNOS), dopamine receptor D2 (DRD2), cyclic adenosine monophosphate (cAMP) response element binding protein-1 (CREB-1) and opioid receptor MU-1 (OPRM-1) genes expression compared with control and LPS-RS treated stressed-mice. As a conclusion, the antagonism of TLR4 could provide therapeutic value in the treatment of stress-induced addiction.
  15. Fulltext The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection
    Che Mohd Nassir CMN, Damodaran T, Ismail NI, Hashim S, Jaffer U, Hamid HA, et al.
    Life (Basel), 2023 Jan 12;13(1).
    PMID: 36676165 DOI: 10.3390/life13010216
    In this narrative review, we present the evidence on nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome activation for its putative roles in the elusive pathomechanism of aging-related cerebral small vessel disease (CSVD). Although NLRP3 inflammasome-interleukin (IL)-1β has been implicated in the pathophysiology of coronary artery disease, its roles in cerebral arteriothrombotic micro-circulation disease such as CSVD remains unexplored. Here, we elaborate on the current manifestations of CSVD and its' complex pathogenesis and relate the array of activators and aberrant activation involving NLRP3 inflammasome with this condition. These neuroinflammatory insights would expand on our current understanding of CSVD clinical (and subclinical) heterogenous manifestations whilst highlighting plausible NLRP3-linked therapeutic targets.
  16. Fulltext COVID-19 Infection and Circulating Microparticles-Reviewing Evidence as Microthrombogenic Risk Factor for Cerebral Small Vessel Disease
    Che Mohd Nassir CMN, Hashim S, Wong KK, Abdul Halim S, Idris NS, Jayabalan N, et al.
    Mol Neurobiol, 2021 Aug;58(8):4188-4215.
    PMID: 34176095 DOI: 10.1007/s12035-021-02457-z
    Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) due to novel coronavirus disease 2019 (COVID-19) has affected the global society in numerous unprecedented ways, with considerable morbidity and mortality. Both direct and indirect consequences from COVID-19 infection are recognized to give rise to cardio- and cerebrovascular complications. Despite current limited knowledge on COVID-19 pathogenesis, inflammation, endothelial dysfunction, and coagulopathy appear to play critical roles in COVID-19-associated cerebrovascular disease (CVD). One of the major subtypes of CVD is cerebral small vessel disease (CSVD) which represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger subsequent neuroinflammation and neurodegeneration. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, and Alzheimer's disease. In the background of COVID-19 infection, the heightened cellular activations from inflammations and oxidative stress may result in elevated levels of microthrombogenic extracellular-derived circulating microparticles (MPs). Consequently, MPs could act as pro-coagulant risk factor that may serve as microthrombi for the vulnerable microcirculation in the brain leading to CSVD manifestations. This review aims to appraise the accumulating body of evidence on the plausible impact of COVID-19 infection on the formation of microthrombogenic MPs that could lead to microthrombosis in CSVD manifestations, including occult CSVD which may last well beyond the pandemic era.
  17. Could protein phosphatase 2A and glycogen synthase kinase-3 beta be targeted by natural compounds to ameliorate Alzheimer's pathologies?
    Manoharan SD, Abdul Hamid H, Md Hashim NF, Cheema MS, Chiroma SM, Mustapha M, et al.
    Brain Res, 2024 Apr 15;1829:148793.
    PMID: 38309553 DOI: 10.1016/j.brainres.2024.148793
    Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and cognitive abilities, primarily in the elderly. The burden of AD extends beyond patients, impacting families and caregivers due to the patients' reliance on assistance for daily tasks. The main features of the pathogenesis of AD are beta-amyloid plaques and neurofibrillary tangles (NFTs), that strongly correlate with oxidative stress and inflammation. NFTs result from misfolded and hyperphosphorylated tau proteins. Various studies have focused on tau phosphorylation, indicating protein phosphatase 2A (PP2A) as the primary tau phosphatase and glycogen synthase kinase-3 beta (GSK-3β) as the leading tau kinase. Experimental evidence suggests that inhibition of PP2A and increased GSK-3β activity contribute to neuroinflammation, oxidative stress, and cognitive impairment. Hence, targeting PP2A and GSK-3β with pharmacological approaches shows promise in treating AD. The use of natural compounds in the drug development for AD have been extensively studied for their antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties, demonstrating therapeutic advantages in neurological diseases. Alongside the development of PP2A activator and GSK-3β inhibitor drugs, natural compounds are likely to have neuroprotective effects by increasing PP2A activity and decreasing GSK-3β levels. Therefore, based on the preclinical and clinical studies, the potential of PP2A and GSK-3β as therapeutic targets of natural compounds are highlighted in this review.
  18. Fulltext Emotion brain network topology in healthy subjects following passive listening to different auditory stimuli
    Mohd Rashid MH, Ab Rani NS, Kannan M, Abdullah MW, Ab Ghani MA, Kamel N, et al.
    PeerJ, 2024;12:e17721.
    PMID: 39040935 DOI: 10.7717/peerj.17721
    A large body of research establishes the efficacy of musical intervention in many aspects of physical, cognitive, communication, social, and emotional rehabilitation. However, the underlying neural mechanisms for musical therapy remain elusive. This study aimed to investigate the potential neural correlates of musical therapy, focusing on the changes in the topology of emotion brain network. To this end, a Bayesian statistical approach and a cross-over experimental design were employed together with two resting-state magnetoencephalography (MEG) as controls. MEG recordings of 30 healthy subjects were acquired while listening to five auditory stimuli in random order. Two resting-state MEG recordings of each subject were obtained, one prior to the first stimulus (pre) and one after the final stimulus (post). Time series at the level of brain regions were estimated using depth-weighted minimum norm estimation (wMNE) source reconstruction method and the functional connectivity between these regions were computed. The resultant connectivity matrices were used to derive two topological network measures: transitivity and global efficiency which are important in gauging the functional segregation and integration of brain network respectively. The differences in these measures between pre- and post-stimuli resting MEG were set as the equivalence regions. We found that the network measures under all auditory stimuli were equivalent to the resting state network measures in all frequency bands, indicating that the topology of the functional brain network associated with emotional regulation in healthy subjects remains unchanged following these auditory stimuli. This suggests that changes in the emotion network topology may not be the underlying neural mechanism of musical therapy. Nonetheless, further studies are required to explore the neural mechanisms of musical interventions especially in the populations with neuropsychiatric disorders.
  19. Commemorating the 40-Year Journey of the School of Medical Sciences, Universiti Sains Malaysia
    Ismail SB, Hassan R, Baharuddin KA, Sulaiman AR, Jaalam K, Wan Hitam WH, et al.
    Malays J Med Sci, 2019 Mar;26(2):1-7.
    PMID: 31447603 DOI: 10.21315/mjms2019.26.2.1
    The School of Medical Sciences of Universiti Sains Malaysia (USM) is the launching pad for this journal. From the school's humble beginning at the USM Main Campus in Pulau Pinang, Malaysia, it has grown in stature at its current location in the USM Health Campus, Kubang Kerian, Kelantan, Malaysia. Commemorating its 40th anniversary, this editorial aims to recollect, although not exhaustively, the wealth of returns for the USM, as well as for the nation, which the school has managed to deliver in that period. Resolute to its vision and mission, this article highlights the outstanding accomplishments in various core aspects of the school's academic, research and professional growth as we continually strive to train globally competitive and compassionate medical graduates, medical specialists and scientists, skilled to serve nation's needs and broader markets worldwide. Currently guided by the Malaysian Higher Education Blueprint (2015-2025), the school shall remain ingenious in its duties in the many more years to come, as we head for a world-class trajectory.
  20. Fulltext Diets and Cellular-Derived Microparticles: Weighing a Plausible Link With Cerebral Small Vessel Disease
    Nassir CMNCM, Ghazali MM, Hashim S, Idris NS, Yuen LS, Hui WJ, et al.
    Front Cardiovasc Med, 2021;8:632131.
    PMID: 33718454 DOI: 10.3389/fcvm.2021.632131
    Cerebral small vessel disease (CSVD) represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger neuroinflammation and the subsequent neurodegenerative cascade. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, Alzheimer disease, and Parkinson disease. Despite being the most common neurodegenerative condition with cerebrocardiovascular axis, understanding about it remains poor. Interestingly, modifiable risk factors such as unhealthy diet including high intake of processed food, high-fat foods, and animal by-products are known to influence the non-neural peripheral events, such as in the gastrointestinal tract and cardiovascular stress through cellular inflammation and oxidation. One key outcome from such events, among others, includes the cellular activations that lead to elevated levels of endogenous cellular-derived circulating microparticles (MPs). MPs can be produced from various cellular origins including leukocytes, platelets, endothelial cells, microbiota, and microglia. MPs could act as microthrombogenic procoagulant that served as a plausible culprit for the vulnerable end-artery microcirculation in the brain as the end-organ leading to CSVD manifestations. However, little attention has been paid on the potential role of MPs in the onset and progression of CSVD spectrum. Corroboratively, the formation of MPs is known to be influenced by diet-induced cellular stress. Thus, this review aims to appraise the body of evidence on the dietary-related impacts on circulating MPs from non-neural peripheral origins that could serve as a plausible microthrombosis in CSVD manifestation as a precursor of neurodegeneration. Here, we elaborate on the pathomechanical features of MPs in health and disease states; relevance of dietary patterns on MP release; preclinical studies pertaining to diet-based MPs contribution to disease; MP level as putative surrogates for early disease biomarkers; and lastly, the potential of MPs manipulation with diet-based approach as a novel preventive measure for CSVD in an aging society worldwide.
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