The effects of metallothionein in paraquat-induced Parkinson disease model of zebrafish.

INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease caused by selective degeneration of dopaminergic neurons in the substantia nigra. Metallothionein has been shown to act as a neuroprotectant in various brain injury. Thus, this study aims to identify the effects of full-length human metallothionein 2 peptide (hMT2) in paraquat-induced brain injury in the zebrafish. METHODOLOGY: A total of 80 adult zebrafish were divided into 4 groups namely control, paraquat-treated, pre-hMT2-treated, and post-hMT2-treated groups. Fish were treated with paraquat intraperitoneally every 3 days for 15 days. hMT2 were injected intracranially on day 0 (pre-treated group) and day 16 (post-treated group). Fish were sacrificed on day 22 and the brains were collected for qPCR, ELISA and immunohistochemistry analysis. RESULTS: qPCR analysis showed that paraquat treatment down-regulated the expression of genes related to dopamine activity and biosynthesis (dat and th1) and neuroprotective agent (bdnf). Paraquat treatment also up-regulated the expression of the mt2, smtb and proinflammatory genes (il-1α, il-1ß, tnf-α and cox-2). hMT2 treatment was able to reverse the effects of paraquat. Lipid peroxidation decreased in the paraquat and pre-hMT2-treated groups. However, lipid peroxidation increased in the post-hMT2-treated group. Paraquat treatment also led to a reduction of dopaminergic neurons while their numbers showed an increase following hMT2 treatment. CONCLUSION: Paraquat has been identified as one of the pesticides that can cause the death of dopaminergic neurons and affect dopamine biosynthesis. Treatment with exogenous hMT2 could reverse the effects of paraquat in the zebrafish brain.

Caffeic Acid on Metabolic Syndrome: A Review.

Metabolic syndrome (MetS) is a constellation of risk factors that may lead to a more sinister disease. Raised blood pressure, dyslipidemia in the form of elevated triglycerides and lowered high-density lipoprotein cholesterol, raised fasting glucose, and central obesity are the risk factors that could lead to full-blown diabetes, heart disease, and many others. With increasing sedentary lifestyles, coupled with the current COVID-19 pandemic, the numbers of people affected with MetS will be expected to grow in the coming years. While keeping these factors checked with the polypharmacy available currently, there is no single strategy that can halt or minimize the effect of MetS to patients. This opens the door for a more natural way of controlling the disease. Caffeic acid (CA) is a phytonutrient belonging to the flavonoids that can be found in abundance in plants, fruits, and vegetables. CA possesses a wide range of beneficial properties from antioxidant, immunomodulatory, antimicrobial, neuroprotective, antianxiolytic, antiproliferative, and anti-inflammatory activities. This review discusses the current discovery of the effect of CA against MetS.

Honey and Alzheimer's Disease-Current Understanding and Future Prospects.

Alzheimer's disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to be attributed by extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles. Additionally, genetic factors such as abnormality in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2 play a role in the disease. As the current treatment aims to treat the symptoms and to slow the disease progression, there has been a continuous search for new nutraceutical agent or medicine to help prevent and cure AD pathology. In this quest, honey has emerged as a powerful nootropic agent. Numerous studies have demonstrated that the high flavonoids and phenolic acids content in honey exerts its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes the effect of main flavonoid compounds found in honey on the physiological functioning of the central nervous system, and the effect of honey intake on memory and cognition in various animal model. This review provides a new insight on the potential of honey to prevent AD pathology, as well as to ameliorate the damage in the developed AD.

Microarray-based analysis of differential gene expression profile in rotenone-induced Parkinson's disease zebrafish model.

BACKGROUND & OBJECTIVES: Despite much clinical and laboratory research that has been performed to explore the mechanisms of Parkinson's disease (PD), its pathogenesis remains elusive to date. Therefore, this study aimed to identify possible regulators of neurodegeneration by performing microarray analysis of the zebrafish PD model's brain following rotenone exposure. METHODS: A total of 36 adult zebrafish were divided into two groups: control (n = 17) and rotenone-treated (n = 19). Fish were treated with rotenone water (5 µg/L water) for 28 days and subjected to locomotor behavior analysis. Total RNA was extracted from the brain tissue after rotenone treatment. The cDNA synthesized was subjected to microarray analysis and subsequently validated by qPCR. RESULTS: Administration of rotenone has significantly reduced locomotor activity in zebrafish (p < 0.05), dysregulated dopamine-related gene expression (dat, th1, and th2, p < 0.001), and reduced dopamine level in the brain (p < 0.001). In the rotenone-treated group, genes involved in cytotoxic T lymphocytes (gzm3, cd8a, p < 0.001) and T cell receptor signaling (themis, lck, p < 0.001) were upregulated significantly. Additionally, gene expression involved in microgliosis regulation (tyrobp, p < 0.001), cellular response to IL-1 (ccl34b4, il2rb, p < 0.05), and regulation of apoptotic process (dedd1, p < 0.001) were also upregulated significantly. CONCLUSION: The mechanisms of T cell receptor signaling, microgliosis regulation, cellular response to IL-1, and apoptotic signaling pathways have potentially contributed to PD development in rotenone-treated zebrafish.

Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD.

Brain volumetric changes in menopausal women and its association with cognitive function: a structured review.

The menopausal transition has been proposed to put women at risk for undesirable neurological symptoms, including cognitive decline. Previous studies suggest that alterations in the hormonal milieu modulate brain structures associated with cognitive function. This structured review provides an overview of the relevant studies that have utilized MRI to report volumetric differences in the brain following menopause, and its correlations with the evaluated cognitive functions. We performed an electronic literature search using Medline (Ovid) and Scopus to identify studies that assessed the influence of menopause on brain structure with MRI. Fourteen studies met the inclusion criteria. Brain volumetric differences have been reported most frequently in the frontal and temporal cortices as well as the hippocampus. These regions are important for higher cognitive tasks and memory. Additionally, the deficit in verbal and visuospatial memory in postmenopausal women has been associated with smaller regional brain volumes. Nevertheless, the limited number of eligible studies and cross-sectional study designs warrant further research to draw more robust conclusions.

Comparable Benefits of Stingless Bee Honey and Caffeic Acid in Mitigating the Negative Effects of Metabolic Syndrome on the Brain.

There is mounting evidence that metabolic syndrome (MetS) contributes to the development of neurodegenerative disorders such as Alzheimer's disease. Honey, which has been used for generations, is high in antioxidants and has been demonstrated to benefit the brain and mental health by reducing oxidative stress and boosting cognitive outcomes. Honey from the stingless bees of Heterotrigona itama has been found to have higher phenolic content compared to other types of honeys. The aim of this study is to investigate the effects of stingless bee honey (SBH) supplementation and to compare it with a pure form of antioxidant, caffeic acid (CA), on MetS parameters and inflammatory markers in the brains of MetS-induced rats. A total of 32 male Wistar rats were divided equally into groups of control, high-carbohydrate high-fructose (HCHF) diet (MetS), HCHF + SBH supplemented (1 g/kg) (SBH), and HCHF + CA supplemented (10 mg/kg) (CA) groups. The total duration for SBH and CA supplementation was eight weeks. The HCHF diet was found to promote hypertension, hyperglycemia, and hypertriglyceridemia, and to increase brain TNF-α levels. Supplementation with SBH and CA significantly reversed (p < 0.05) the hyperglycemic and hypertensive effects of the HCHF diet. Although both supplemented groups showed no significant changes to serum HDL or TG, SBH significantly reduced (p < 0.05) brain TNF-α levels and increased (p < 0.05) brain BDNF levels. Immunohistochemistry investigations of neurogenesis (EdU) and apoptosis (TUNEL) on the cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus showed no changes with SBH and CA supplementation compared to the control. These findings suggest that SBH and CA have the potential to mitigate HCHF-induced MetS effects and possess neuroprotective abilities.

Goofballing of Opioid and Methamphetamine: The Science Behind the Deadly Cocktail.

Globally, millions of people suffer from various substance use disorders (SUD), including mono-and polydrug use of opioids and methamphetamine. Brain regions such as the cingulate cortex, infralimbic cortex, dorsal striatum, nucleus accumbens, basolateral and central amygdala have been shown to play important roles in addiction-related behavioral changes. Clinical and pre-clinical studies have characterized these brain regions and their corresponding neurochemical changes in numerous phases of drug dependence such as acute drug use, intoxication, craving, withdrawal, and relapse. At present, many studies have reported the individual effects of opioids and methamphetamine. However, little is known about their combined effects. Co-use of these drugs produces effects greater than either drug alone, where one decreases the side effects of the other, and the combination produces a prolonged intoxication period or a more desirable intoxication effect. An increasing number of studies have associated polydrug abuse with poorer treatment outcomes, drug-related deaths, and more severe psychopathologies. To date, the pharmacological treatment efficacy for polydrug abuse is vague, and still at the experimental stage. This present review discusses the human and animal behavioral, neuroanatomical, and neurochemical changes underlying both morphine and methamphetamine dependence separately, as well as its combination. This narrative review also delineates the recent advances in the pharmacotherapy of mono- and poly drug-use of opioids and methamphetamine at clinical and preclinical stages.

MicroRNA Dysregulation in Parkinson's Disease: A Narrative Review.

Parkinson's disease (PD) is a severely debilitating neurodegenerative disease, affecting the motor system, leading to resting tremor, cogwheel rigidity, bradykinesia, walking and gait difficulties, and postural instability. The severe loss of dopaminergic neurons in the substantia nigra pars compacta causes striatal dopamine deficiency and the presence of Lewy bodies indicates a pathological hallmark of PD. Although the current treatment of PD aims to preserve dopaminergic neurons or to replace dopamine depletion in the brain, it is notable that complete recovery from the disease is yet to be achieved. Given the complexity and multisystem effects of PD, the underlying mechanisms of PD pathogenesis are yet to be elucidated. The advancement of medical technologies has given some insights in understanding the mechanism and potential treatment of PD with a special interest in the role of microRNAs (miRNAs) to unravel the pathophysiology of PD. In PD patients, it was found that striatal brain tissue and dopaminergic neurons from the substantia nigra demonstrated dysregulated miRNAs expression profiles. Hence, dysregulation of miRNAs may contribute to the pathogenesis of PD through modulation of PD-associated gene and protein expression. This review will discuss recent findings on PD-associated miRNAs dysregulation, from the regulation of PD-associated genes, dopaminergic neuron survival, α-synuclein-induced inflammation and circulating miRNAs. The next section of this review also provides an update on the potential uses of miRNAs as diagnostic biomarkers and therapeutic tools for PD.

Stingless Bee Honey Reduces Anxiety and Improves Memory of the Metabolic Disease-induced Rats.

BACKGROUND: Scientific studies support the evidence of the involvement of Metabolic Syndrome (MetS) in the progression of neurodegenerative diseases through oxidative stress. Consumption of antioxidant compounds was found to be beneficial for brain-health as it reduced the brain oxidative stress level and improved cognitive performance in animals. Stingless bee honey or locally known as Kelulut Honey (KH) has high phenolic content and is widely used as a food supplement. OBJECTIVES: In this study, we aimed to investigate the effects of KH on the brain of MetS-induced rats. METHODS: Forty male Wistar rats were divided into 5 groups; 8 weeks (C8) and 16 weeks control groups (C16), groups that received High-Carbohydrate High Fructose (HCHF) diet for 8 weeks (MS8) and 16 weeks (MS16), and a group that received HCHF for 16 weeks with KH supplemented for the last 35 days (KH). RESULTS: Serum fasting blood glucose decreased in the KH group compared to the MS16 group. HDL levels were significantly decreased in MetS groups compared to control groups. Open field experiments showed that KH group exhibits less anxious behavior compared to the MetS group. Probe trial of Morris water maze demonstrated significant memory retention of KH group compared to the MS16 group. Nissl staining showed a significant decrease in the pyramidal hippocampal cells in the MS16 compared to the KH group. CONCLUSION: KH has the ability to normalise blood glucose and reduce serum triglyceride and LDL levels in MetS rats, while behavior studies complement its effect on anxiety and memory. This shows a promising role of KH in attenuating neurodegenerative diseases through the antioxidant activity of its polyphenolic content.

A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases.

Nutraceuticals have been extensively studied worldwide due to its neuroprotective effects in in vivo and in vitro studies, attributed by the antioxidative properties. Alzheimer (AD) and Parkinson disease (PD) are the two main neurodegenerative disorders that are discussed in this review. Both AD and PD share the similar involvement of oxidative stress in their pathophysiology. Nutraceuticals exert their antioxidative effects via direct scavenging of free radicals, prevent damage to biomolecules, indirectly stimulate the endogenous antioxidative enzymes and gene expressions, inhibit activation of pro-oxidant enzymes, and chelate metals. In addition, nutraceuticals can act as modulators of pro-survival, pro-apoptotic, and inflammatory signaling pathways. They have been shown to be effective particularly in preclinical stages, due to their multiple mechanisms of action in attenuating oxidative stress underlying AD and PD. Natural antioxidants from food sources and natural products such as resveratrol, curcumin, green tea polyphenols, and vitamin E are promising therapeutic agents in oxidative stress-mediated neurodegenerative disease as they have fewer adverse effects, more tolerable, cheaper, and sustainable for long term consumption.

Abelmoschus Esculentus (L.) Moench's Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice.

Okra peel exhibits numerous therapeutic effects. This study explores the potential ameliorative effects of okra peel powder on high-fat-diet (HFD)-induced hypercholesterolemia and cognitive deficits. Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group): (i) control, mice fed with a normal diet; (ii) HFD, mice fed with HFD; (iii) HFD-SIM, mice fed with HFD and given simvastatin (20 mg/kg/day); (iv) HFD-OP1; (v) HFD-OP2; (vi) HFD-OP3, mice fed with HFD and okra peel (200, 400, or 800 mg/kg/day, respectively). Following 10 weeks of treatments, the mice were subjected to the Morris water maze (MWM). Parameters such as weekly average body weight, food intake, and blood lipid profiles were also recorded. The HFD group showed a profound increase in total cholesterol and low-density lipoprotein concentration compared to the control group. All okra-treated and HFD-SIM groups performed better than the HFD group during acquisition trials, whereas only the HFD-OP1 produced a significantly higher number of entries into the platform zone during the probe trial. In sum, all three okra doses improved the learning ability of the mice. However, only the lowest dose of okra significantly improved the spatial reference memory retention.

Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty.

Alzheimer's disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD is one of the biggest medical, economic, and social concerns to patients and their caregivers. AD was ranked as the 5th leading cause of global deaths in 2016 by the World Health Organization (WHO). Many drugs targeting the production, aggregation, and clearance of Aß plaques failed to give any conclusive clinical outcomes. This mainly stems from the fact that AD is not a disease attributed to a single-gene mutation. Two hallmarks of AD, Aß plaques and neurofibrillary tangles (NFTs), can simultaneously induce other AD etiologies where every pathway is a loop of consequential events. Therefore, the focus of recent AD research has shifted to exploring other etiologies, such as neuroinflammation and central hyperexcitability. Neuroinflammation results from the hyperactivation of microglia and astrocytes that release pro-inflammatory cytokines due to the neurological insults caused by Aß plaques and NFTs, eventually leading to synaptic dysfunction and neuronal death. This review will report the failures and side effects of many anti-Aß drugs. In addition, emerging treatments targeting neuroinflammation in AD, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and receptor-interacting serine/threonine protein kinase 1 (RIPK1), that restore calcium dyshomeostasis and microglia physiological function in clearing Aß plaques, respectively, will be deliberately discussed. Other novel pharmacotherapy strategies in treating AD, including disease-modifying agents (DMTs), repurposing of medications used to treat non-AD illnesses, and multi target-directed ligands (MTDLs) are also reviewed. These approaches open new doors to the development of AD therapy, especially combination therapy that can cater for several targets simultaneously, hence effectively slowing or stopping AD.

Construction of an Affordable Open-Design Recirculating Zebrafish Housing System.

Recently, the zebrafish has gained in popularity as a vertebrate animal model for biomedical research. Commercial zebrafish housing systems are available and are designed to maximize stocking density of fish for a given space, but these systems are expensive and purchasing them may not be feasible for emerging laboratories with limited funding. In this article, we describe the construction of a simple and affordable recirculating zebrafish housing system. This system can be constructed in 3 working days, with materials readily available in hardware stores. The cost for construction of the system was only 3,000 MYR (750 USD). The system consists of a water reservoir, a supply line that delivers water to the shelves holding the zebrafish tanks, and a drainage line that receives water from both the supply line and the shelves containing the fish tanks and returns this water to the reservoir. This system also has a 3-stage filtration process to ensure that clean water is delivered to the zebrafish tank. The system can house up to 360 zebrafish. This low-cost housing system may make research using zebrafish feasible some laboratories.

Metabolic Syndrome and Its Effect on the Brain: Possible Mechanism.

BACKGROUND & OBJECTIVE: Metabolic syndrome (MetS) is an interconnected group of physiological, biochemical, clinical and metabolic factors that directly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) and mortality. Rising evidence suggests that MetS plays a significant role in the progression of Alzheimer's disease and other neurodegenerative diseases. Nonetheless, the factors linking this association has not yet been elucidated. As we are facing an increasing incidence of obesity and T2DM in all stages of life, understanding the association of MetS and neurodegenerative diseases is crucial to lessen the burden of the disease. CONCLUSION: In this review, we will discuss the possible mechanisms which may relate the association between MetS and cognitive decline which include vascular damages, elevation of reactive oxygen species (ROS), insulin resistance and low-grade inflammation.

Herbs for Effective Treatment of Diabetes Mellitus Wounds: Medicinal Chemistry and Future Therapeutic Options.

The incidence of diabetes mellitus (DM) has increased globally. Various complications such as blindness, nephropathy leading to renal failure, neuropathy, foot ulceration, amputation, and disturbance in autonomic nervous system were reported. Although, allopathy treatment still remains the treatment of choice, there is a need to look at the easy availability, patient compliance and cheaper cost of the drugs used in day-day practice. In this regard, complementary and alternative medicine has a greater role to play. Numerous plant extracts were shown to exhibit antihyperglycemic properties. In the present review, we surfed published literature in Pubmed and google databases with regard to the herbs used for DM wound treatment. We also discuss the possible mechanism of wound healing in DM with regard to advanced glycation end products, inflammation, macrophages, non-leukocytic cells such as keratinocytes, fibroblasts and endothelial cells, matrix metalloproteinase and miRNA. The review opens the door for effective treatment of DM wounds with plant extracts and plan future treatment options.

Flavonoids and its Neuroprotective Effects on Brain Ischemia and Neurodegenerative Diseases.

Brain ischemia is among the leading cause of death with majority of the cases are associated with ischemic strokes. It can occur in two forms of either focal or global ischemia. Neurodegenerative disorder such as Alzheimer and Parkinson diseases is also on the rise worldwide. These disorders have common similarities; i.e. they all affecting the central nervous system with debilitating effect to the patient. In this review, we look into the promising role of flavonoids, a natural bioactive compound found abundant in vegetables, fruits and traditional herbs. Treatment with flavonoids such as curcumin, lycopene, ginsenoside, vitexin and baicalin have shown promising neuroprotective effects against ischemic-induced injury. Besides anticancer, antioxidant and immunomodulation properties, flavonoid also exerts neuroprotective effects by increases neuronal viability, increases tissue perfusion and cerebral blood flow and reduce ischemic-related apoptosis. In addition, flavonoid also exerts anti-amyloidogenic effect and reduces loss of dopaminergic neurons in the brain. These results suggesting flavonoids might be able to serve as a potential therapeutic agent in brain disorders.

Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-ß peptide (Aß). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPα), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Αß, sAPPα has many neuroprotective and neurotrophic properties. Increasing sAPPα levels has the potential to serve as a therapeutic treatment that mitigates the effects of Aß and rescue cognitive function. Here we tested the hypothesis that lentivirus-mediated expression of a human sAPPα construct in a mouse model of AD (APPswe/PS1dE9), begun before the onset of plaque pathology, could prevent later behavioural and electrophysiological deficits. Male mice were given bilateral intra-hippocampal injections at 4 months of age and tested 8-10 months later. Transgenic mice expressing sAPPα performed significantly better than untreated littermates in all aspects of the spatial water maze task. Expression of sAPPα also resulted in partial rescue of long-term potentiation (LTP), tested in vitro. These improvements occurred in the absence of changes in amyloid pathology. Supporting these findings on LTP, lentiviral-mediated expression of sAPPα for 3 months from 10 months of age, or acute sAPPα treatment in hippocampal slices from 18 to 20 months old transgenic mice, completely reversed the deficits in LTP. Together these findings suggest that sAPPα has wide potential to act as either a preventative or restorative therapeutic treatment in AD by mitigating the effects of Aß toxicity and enhancing cognitive reserve.