Recent progress on anti-nociceptive effects of carbon monoxide releasing molecule-2 (CORM-2).

The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.

Minocycline Protects Against Lipopolysaccharide-Induced Cognitive Impairment and Oxidative Stress: Possible Role of the CREB-BDNF Signaling Pathway.

The oxidative stress-induced dysregulation of the cyclic AMP response element-binding protein- brain-derived neurotrophic factor (CREB-BDNF) cascade has been linked to cognitive impairment in several studies. This study aimed to investigate the effect of minocycline on the levels of oxidative stress markers, CREB, and BDNF in lipopolysaccharide (LPS)-induced cognitive impairment. Fifty adult male Sprague Dawley rats were divided randomly into five groups. Group 1 was an untreated control group. Groups 2, 3, 4 and 5 were treated concurrently with LPS (5 mg/kg, i.p) once on day 5 and normal saline (0.7 ml/rat, i.p) or minocycline (25 and 50 mg/kg, i.p) or memantine (10 mg/kg, i.p) once daily from day 1 until day 14, respectively. From day 15 to day 22 of the experiment, Morris Water Maze (MWM) was used to evaluate learning and reference memory in rats. The levels of protein carbonyl (PCO), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were determined by enzyme-linked immunosorbent assay (ELISA). CREB and BDNF expression and density were measured by immunohistochemistry and western blot analysis, respectively. LPS administration significantly increased escape latency to the hidden platform with decreased travelled distance, swimming speed, target crossings and time spent in the target quadrant. Besides, the hippocampal tissue of LPS rats showed increased levels of PCO and MDA, decreased levels of CAT and SOD, and reduced expression and density of BDNF and CREB. Treatment with minocycline reversed these effects in a dose-dependent manner, comparable to the effects of memantine. Both doses of minocycline treatment protect against LPS-induced cognitive impairment by reducing oxidative stress and upregulating the CREB-BDNF signalling pathway in the rat hippocampus.

Thematic analysis of multiple sclerosis research by enhanced strategic diagram.

Recent interest in multiple sclerosis research warrants literature analysis to evaluate the current state of the discipline and new research domains. This bibliometric review summarised the research trends and analysed research areas in multiple sclerosis over the last decade. The documents containing the term 'multiple sclerosis' in the article title were retrieved from the Scopus database. We used Harzing's Publish or Perish and VOSviewer for citation analysis and data visualisation, respectively. We found a total of 18,003 articles published in journals in the English language between 2012 and 2021. The emerging keywords identified utilising the enhanced strategic diagram were 'covid-19', 'teriflunomide', 'clinical trial', 'microglia', 'b cells', 'myelin', 'brain', 'white matter', 'functional connectivity', 'pain', 'employment', 'health-related quality of life', 'meta-analysis' and 'comorbidity'. This study demonstrates the tremendous growth of multiple sclerosis literature worldwide, which is expected to grow more than double during the next decade especially in the identified emerging topics.

Minocycline protects against lipopolysaccharide-induced glial cells activation and oxidative stress damage in the medial prefrontal cortex (mPFC) of the rat.

PURPOSE/AIM: Neuroinflammation and oxidative stress have been encountered in neurodegenerative diseases such as Alzheimer's disease (AD). However, the neuroprotective effects of minocycline against lipopolysaccharide (LPS)-induced glial cells activation and oxidative stress damage in the medial prefrontal cortex (mPFC) of rats are still elusive. The purpose of this study is to investigate the effects of minocycline and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on the microglia and astrocytes expression, as well as oxidative stress levels in the mPFC of LPS injected rats. MATERIALS AND METHODS: Fifty adult Male Sprague Dawley rats were divided into five groups: control, LPS (5 mg/kg), LPS treated with minocycline (25 mg/kg), LPS treated with minocycline (50 mg/kg) and LPS treated with memantine (10 mg/kg). The immunohistochemistry and western blotting were used to analyse the expressions and densities of microglia marker (Iba-1) and astrocyte marker, (GFAP) while enzyme-linked immunosorbent assay (ELISA) was used to measure the protein carbonyl (PCO), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) levels. RESULTS: In comparison to the control group, the expression and density of Iba-1 and GFAP were significantly enhanced in the LPS group (p < 0.05). LPS group also exhibited significantly higher levels of PCO and MDA (p < 0.05) and significantly lower levels of CAT and SOD (p < 0.05) when compared to the control group. Both minocycline and memantine-treated LPS rats were able to protect against these effects. CONCLUSION: Minocycline, like memantine treatment, reduces oxidative stress in the mPFC of LPS rats via inhibition of glial cells activation.

Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.

Minocycline Attenuates Lipopolysaccharide-Induced Locomotor Deficit and Anxiety-like Behavior and Related Expression of the BDNF/CREB Protein in the Rat Medial Prefrontal Cortex (mPFC).

Neuroinflammation following lipopolysaccharide (LPS) administration induces locomotor deficits and anxiety-like behaviour. In this study, minocycline was compared to memantine, an NMDA receptor antagonist, for its effects on LPS-induced locomotor deficits and anxiety-like behaviour in rats. Adult male Sprague Dawley rats were administered either two different doses of minocycline (25 or 50 mg/kg/day, i.p.) or 10 mg/kg/day of memantine (i.p.) for 14 days four days prior to an LPS (5 mg/kg, i.p.) injection. Locomotor activity and anxiety-like behaviour were assessed using the open-field test (OFT). The phosphorylated tau protein level was measured using ELISA, while the expression and density of brain-derived neurotrophic factor (BDNF) and cAMP response element-binding (CREB) protein in the medial prefrontal cortex (mPFC) were measured using immunohistochemistry and Western blot, respectively. Minocycline treatment reduced locomotor deficits and anxiety-like behaviour associated with reduced phosphorylated tau protein levels, but it upregulated BDNF/CREB protein expressions in the mPFC in a comparable manner to memantine, with a higher dose of minocycline having better benefits. Minocycline treatment attenuated LPS-induced locomotor deficits and anxiety-like behaviour in rats and decreased phosphorylated tau protein levels, but it increased the expressions of the BDNF/CREB proteins in the mPFC.

The role of mTOR signalling pathway in hypoxia-induced cognitive impairment.

Hypoxia has been associated with cognitive impairment. Many studies have investigated the role of mTOR signalling pathway in cognitive functions but its role in hypoxia-induced cognitive impairment remains controversial. This review aimed to elucidate the role of mTOR in the mechanisms of cognitive impairment that may pave the way towards the mechanistic understanding and therapeutic intervention of hypoxia-induced cognitive impairment. mTORC1 is normally regulated during mild or acute hypoxic exposure giving rise to neuroprotection, whereas it is overactivated during severe or chronic hypoxia giving rise to neuronal cells death. Thus, it is worth exploring the possibility of maintaining normal mTORC1 activity and thereby preventing cognitive impairment during severe or chronic hypoxia.

Tualang Honey: A Decade of Neurological Research.

Tualang honey has been shown to protect against neurodegeneration, leading to improved memory/learning as well as mood. In addition, studies have also demonstrated its anti-inflammatory and antioxidant properties. However, a substantial part of this research lacks systematization, and there seems to be a tendency to start anew with every study. This review presents a decade of research on Tualang honey with a particular interest in the underlying mechanisms related to its effects on the central nervous system. A total of 28 original articles published between 2011 and 2020 addressing the central nervous system (CNS) effects of Tualang honey were analysed. We identified five main categories, namely nootropic, antinociceptive, stress-relieving, antidepressant, and anxiolytic effects of Tualang honey, and proposed the underlying mechanisms. The findings from this review may potentially be beneficial towards developing new therapeutic roles for Tualang honey and help in determining how best to benefit from this brain supplement.

Parcellation of the Hippocampus According to Its Connection Probability with Prefrontal Cortex Subdivisions in a Malaysian Malay Population: Preliminary Findings.

BACKGROUND: Lesion studies have shown distinct roles for the hippocampus, with the dorsal subregion being involved in processing of spatial information and memory, and the ventral aspect coding for emotion and motivational behaviour. However, its structural connectivity with the subdivisions of the prefrontal cortex (PFC), the executive area of the brain that also has various distinct functions, has not been fully explored, especially in the Malaysian population. METHODS: We performed diffusion magnetic resonance imaging with probabilistic tractography on four Malay males to parcellate the hippocampus according to its relative connection probability to the six subdivisions of the PFC. RESULTS: Our findings revealed that each hippocampus showed putative connectivity to all the subdivisions of PFC, with the highest connectivity to the orbitofrontal cortex (OFC). Parcellation of the hippocampus according to its connection probability to the six PFC subdivisions showed variability in the pattern of the connection distribution and no clear distinction between the hippocampal subregions. CONCLUSION: Hippocampus displayed highest connectivity to the OFC as compared to other PFC subdivisions. We did not find a unifying pattern of distribution based on the connectivity-based parcellation of the hippocampus.

Goat milk attenuates mimetic aging related memory impairment via suppressing brain oxidative stress, neurodegeneration and modulating neurotrophic factors in D-galactose-induced aging model.

One of the most significant hallmarks of aging is cognitive decline. D-galactose administration may impair memory and mimic the effects of natural aging. In this study, the efficiency of goat milk to protect against memory decline was tested. Fifty-two male Sprague-Dawley rats were randomly divided into four groups: (i) control group, (ii) goat milk treated group, (iii) D-galactose treated group, and (iv) goat milk plus D-galactose treated group. Subcutaneous injections of D-galactose at 120 mg/kg and oral administrations of goat milk at 1 g/kg were chosen for the study. Goat milk and D-galactose were administered concomitantly for 6 weeks, while the control group received saline. After 6 weeks, novel object recognition and T-maze tests were performed to evaluate memory of rats. Following behavioral tests, the animals were sacrificed, and right brain homogenates were analyzed for levels of lipid peroxidation, antioxidant enzymes and neurotrophic factors. The left brain hemisphere was used for histological study of prefrontal cortex and hippocampus. There was a significant memory impairment, an increase in oxidative stress and neurodegeneration and a reduction in antioxidant enzymes and neurotrophic factors levels in the brain of D-galactose treated rats compared to controls. Goat milk treatment attenuated memory impairment induced by D-galactose via suppressing oxidative stress and neuronal damage and increasing neurotrophic factors levels, thereby suggesting its potential role as a geroprotective food.

In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors.

Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC50 of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from Centella asiatica, revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC50 values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.

Six Months Guided Exercise Therapy Improves Motor Abilities and White Matter Connectivity in Children with Cerebral Palsy.

BACKGROUND: Diffusion magnetic resonance imaging (dMRI) provides the state of putative connectivity from lesioned areas to other brain areas and is potentially beneficial to monitor intervention outcomes. This study assessed the effect of a 6 months guided exercise therapy on motor abilities and white matter diffusivity in the brains of cerebral palsy (CP) children. METHODS: This is a single arm pre-and post-test research design involving 10 spastic CP children, aged 8-18 years and whose Gross Motor Function Classification System Expanded and Revised (GMFCS-E & R) at least Level 21 with the ability to ambulate independently. They were recruited from Paediatric Neurology Clinic, Hospital Universiti Sains Malaysia (HUSM) from December 2015-December 2016. All participants underwent 6 months of therapist-guided exercise session comprising progressive strength training at a frequency of twice a week, 1 h duration per session. The effect of exercise on motor abilities was assessed using the Gross Motor Function Measures (GMFM)-88. Six out of the 10 children consented for dMRI. Probabilistic tractography of the corticospinal tract (CST) was performed to determine the connectivity index of the tracts pre-and post-intervention. RESULTS: All the participants displayed statistically significant increment in GMFM-88 scores pre-to post-exercise intervention. This improvement was concurrent with increased connectivity index in the CST of upper limbs and lower limbs in the brain of these children. CONCLUSION: Our findings demonstrated that 6 months guided exercise therapy improves motor abilities of CP children concurrent with strengthening the connectivities of the motor pathways in the brain.

D-Galactose-induced accelerated aging model: an overview.

To facilitate the process of aging healthily and prevent age-related health problems, efforts to properly understand aging mechanisms and develop effective and affordable anti-aging interventions are deemed necessary. Systemic administration of D-galactose has been established to artificially induce senescence in vitro and in vivo as well as for anti-aging therapeutic interventions studies. The aim of this article is to comprehensively discuss the use of D-galactose to generate a model of accelerated aging and its possible underlying mechanisms involved in different tissues/organs.

Characterisation of the Corticospinal Tract Using Diffusion Magnetic Resonance Imaging in Unilateral and Bilateral Cerebral Palsy Patients.

BACKGROUND: Neuroimaging is increasingly used to locate the lesion that causes cerebral palsy (CP) and its extent in the brains of CP patients. Conventional structural magnetic resonance imaging (MRI) does not indicate the connectional pattern of white matter; however, with the help of diffusion MRI, fibre tracking of white matter can be done. METHODS: We used diffusion MRI and probabilistic tractography to identify the putative white matter connectivity in the brains of 10 CP patients. We tracked the corticospinal tract (CST) of the patients' upper and lower limbs and calculated the white matter connectivity, as indexed by streamlines representing the probability of connection of the CST. RESULTS: Our results show that diffusion MRI with probabilistic tractography, while having some relation with the clinical diagnosis of CP, reveals a high degree of individual variation in the streamlines representing the CST for upper and lower limbs. CONCLUSION: Diffusion MRI with probabilistic tractography provides the state of connectivity from lesioned areas to other parts of the brain and is potentially beneficial to be used as an adjunct to the clinical management of CP, providing a means to monitor intervention outcomes.

Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress.

Recent evidence has exhibited dietary influence on the manifestation of different types of behavior induced by stressor tasks. The present study examined the effects of Tualang honey supplement administered with the goal of preventing or attenuating the occurrence of stress-related behaviors in male rats subjected to noise stress. Forty-eight adult male rats were randomly divided into the following four groups: i) nonstressed with vehicle, ii) nonstressed with Tualang honey, iii) stressed with vehicle, and iv) stressed with honey. The supplement was given once daily via oral gavage at 0.2 g/kg body weight. Two types of behavioral tests were performed, namely, the novel object recognition test to evaluate working memory and the forced swimming test to evaluate depressive-like behavior. Data were analyzed by a two-way analysis of variance (ANOVA) using IBM SPSS 18.0. It was observed that the rats subjected to noise stress expressed higher levels of depressive-like behavior and lower memory functions compared to the unexposed control rats. In addition, our results indicated that the supplementation regimen successfully counteracted the effects of noise stress. The forced swimming test indicated that climbing and swimming times were significantly increased and immobility times significantly decreased in honey-supplemented rats, thereby demonstrating an antidepressant-like effect. Furthermore, cognitive function was shown to be intensely affected by noise stress, but the effects were counteracted by the honey supplement. These findings suggest that subchronic exposure to noise stress induces depressive-like behavior and reduces cognitive functions, and that these effects can be attenuated by Tualang honey supplementation. This warrants further studies to examine the role of Tulang honey in mediating such effects.

Pain in Times of Stress.

Stress modulates pain perception, resulting in either stress-induced analgesia or stress-induced hyperalgesia, as reported in both animal and human studies. The responses to stress include neural, endocrine, and behavioural changes, and built-in coping strategies are in place to address stressors. Peculiar to humans are additional factors that modulate pain that are experienced in times of stress, notably psychological factors that potentially influence the directionality of pain perception.

Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen.

A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF) expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 17 ß -estradiol (E2) on the depressive-like behaviour, stress hormones, and BDNF concentration in stressed ovariectomised (OVX) rats. The animals were divided into six groups: (i) nonstressed sham-operated control, (ii) stressed sham-operated control, (iii) nonstressed OVX, (iv) stressed OVX, (v) stressed OVX treated with E2 (20 µg daily, sc), and (vi) stressed OVX treated with Tualang honey (0.2 g/kg body weight daily, orally). Two months after surgery, the animals were subjected to social instability stress procedure followed by forced swimming test. Struggling time, immobility time, and swimming time were scored. Serum adrenocorticotropic hormone (ACTH) and corticosterone levels, and the BDNF concentration were determined using commercially available ELISA kits. Stressed OVX rats displayed increased depressive-like behaviour with significantly increased serum ACTH and corticosterone levels, while the BDNF concentration was significantly decreased compared to other experimental groups. These changes were notably reversed by both E2 and Tualang honey. In conclusion, both Tualang honey and E2 mediate antidepressive-like effects in stressed OVX rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis and enhancement of the BDNF concentration.

Minocycline mitigates tau pathology via modulating the TLR-4/NF-Ðºß signalling pathway in the hippocampus of neuroinflammation rat model.

INTRODUCTION: The neuroinflammatory response was seen to impact the formation of phosphorylated tau protein in Alzheimer's disease (AD). This study aims to investigate the molecular mechanism of minocycline in reducing phosphorylated tau protein formation in the hippocampus of lipopolysaccharide (LPS)-induced rats. METHODS: Fifty adult male Sprague Dawley (SD) rats were randomly allocated to 1 of 5 groups: control, LPS (5 mg/kg), LPS + minocycline (25 mg/kg), LPS + minocycline (50 mg/kg) and LPS + memantine (10 mg/kg). Minocycline and memantine were administered intraperitoneally (i.p) for two weeks, and LPS was injected i.p. once on day 5. ELISA was used to determine the level of phosphorylated tau protein in SD rats' hippocampal tissue. The density and expression of Toll-like receptor-4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кß), tumour necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2 were determined using Western blot and immunohistochemistry. RESULTS: Minocycline, like memantine, prevented LPS-induced increasein phosphorylated tau protein level suggested via reduced density and expression of TLR-4, NF-кß, TNF-αand COX-2 proteins in rat hippocampal tissue. Interestingly, higher doses were shown to be more neuroprotective than lower doses. CONCLUSION: This study suggests that minocycline suppresses the neuroinflammation signalling pathway and decreased phosphorylated tau protein formation induced by LPS in a dose-dependent manner. Minocycline can be used as a preventative and therapeutic drug for neuroinflammatory diseases such as AD.

Brain-derived neurotrophic factor (BDNF) in chronic pain research: A decade of bibliometric analysis and network visualization.

Chronic pain research, with a specific focus on the brain-derived neurotrophic factor (BDNF), has made impressive progress in the past decade, as evident in the improved research quality and increased publications. To better understand this evolving landscape, a quantitative approach is needed. The main aim of this study is to identify the hotspots and trends of BDNF in chronic pain research. We screened relevant publications from 2013 to 2022 in the Scopus database using specific search subject terms. A total of 401 documents were selected for further analysis. We utilized several tools, including Microsoft Excel, Harzing's Publish or Perish, and VOSViewer, to perform a frequency analysis, citation metrics, and visualization, respectively. Key indicators that were examined included publication growth, keyword analyses, topmost influential articles and journals, networking by countries and co-citation of cited references. Notably, there was a persistent publication growth between 2015 and 2021. "Neuropathic pain" emerged as a prominent keyword in 2018, alongside "microglia" and "depression". The journal Pain® was the most impactful journal that published BDNF and chronic pain research, while the most influential publications came from open-access reviews and original articles. China was the leading contributor, followed by the United States (US), and maintained a leadership position in the total number of publications and collaborations. In conclusion, this study provides a comprehensive list of the most influential publications on BDNF in chronic pain research, thereby aiding in the understanding of academic concerns, research hotspots, and global trends in this specialized field.

Global research Activity on olfactory marker protein (OMP): A bibliometric and visualized analysis.

Olfactory marker protein (OMP) is extensively studied in mature olfactory receptor neurons (ORNs) for understanding olfaction physiology. However, no bibliometric analysis on this topic exists. We conducted a bibliometric analysis of OMP research articles, wherein the publication count was assessed by year, country, journal, and author, collaboration by country, and productivity of the authors. Additionally, key terms and research themes were identified. Using the search phrase "olfactory marker protein" in Scopus, we retrieved 691 original research articles by 2487 authors since 1974. Publications showed an increasing trend, with the United States leading in quantity and collaboration. Our thematic map highlights "Olfactory bulb, regeneration, olfactory" as the primary research domain, while "olfaction, olfactory sensory neuron, glomerulus" and "olfactory receptor neurons, apoptosis, olfactory dysfunction" emerge as essential future research topics. These bibliometric findings offer insights into the global OMP research landscape, guiding researchers in potential collaborations and intriguing future research fields.