Dopaminergic Perturbation in the Aetiology of Neurodevelopmental Disorders.

Brain development may be influenced by both genetic and environmental factors, with potential consequences that may last through the lifespan. Alterations during neurogenesis are linked to neurodevelopmental cognitive disorders. Many neurotransmitters and their systems play a vital role in brain development, as most are present prior to synaptogenesis, and they are involved in the aetiology of many neurodevelopmental disorders. For instance, dopamine (DA) receptor expression begins at the early stages of development and matures at adolescence. The long maturation period suggests how important it is for the stabilisation and integration of neural circuits. DA and dopaminergic (DAergic) system perturbations have been implicated in the pathogenesis of several neurological and neuropsychiatric disorders. The DAergic system controls key cognitive and behavioural skills including emotional and motivated behaviour through DA as a neurotransmitter and through the DA neuron projections to major parts of the brain. In this review, we summarise the current understanding of the DAergic system's influence on neurodevelopment and its involvement in the aetiology and progression of major disorders of the developing brain including autism, schizophrenia, attention deficit hyperactivity disorder, down syndrome, and fragile X syndrome.

Ferulic acid mitigates diabetic cardiomyopathy via modulation of metabolic abnormalities in cardiac tissues of diabetic rats.

Cardiovascular abnormalities have been reported as a major contributor of diabetic mortality. The protective effect of ferulic acid on diabetic cardiomyopathy in fructose-streptozotocin induced type 2 diabetes (T2D) rat model was elucidated in this study. Type 2 diabetic rats were treated by oral administration of low (150 mg/kg b.w) and high (300 mg/kg b.w) doses of ferulic acid. Metformin was used as the antidiabetic drug. Rats were humanely euthanized after 5 weeks of treatment, and their blood and hearts were collected. Induction of T2D depleted the levels of reduced glutathione, glycogen, and HDL-cholesterol and the activities of superoxide dismutase, catalase, ENTPDase, and 5'nucleotidase. It simultaneously triggered increase in the levels of malondialdehyde, total cholesterol, triglyceride, LDL-cholesterol, creatinine kinase-MB as well as activities of acetylcholinesterase, angiotensin converting enzyme (ACE), ATPase, glucose-6-phopsphatase, fructose-1,6-bisphophatase, glycogen phosphorylase, and lipase. T2D induction further revealed an obvious degeneration of cardiac muscle morphology. However, treatment with ferulic acid markedly reversed the levels and activities of these biomarkers with concomitant improvement in myocardium structural morphology, which had favorable comparison with the standard drug, metformin. Additionally, T2D induction led to the depletion of 40%, 75%, and 33% of fatty acids, fatty esters, and steroids, respectively, with concomitant generation of eicosenoic acid, gamolenic acid, and vitamin E. Ferulic acid treatment restored eicosanoic acid, 2-hydroxyethyl ester, with concomitant generation of 6-octadecenoic acid, (Z)-, cis-11-eicosenoic acid, tridecanedioic acid, octadecanoic acid, 2-hydroxyethyl ester, ethyl 3-hydroxytridecanoate, dipalmitin, cholesterol isocaproate, cholest-5-ene, 3-(1-oxobuthoxy)-, cholesta-3,5-diene. These results suggest the cardioprotective potential of ferulic acid against diabetic cardiomyopathy.

Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure.

Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.

ERK/MAPK signalling in the developing brain: Perturbations and consequences.

The extracellular regulated kinase/microtubule-associated protein kinase (ERK/MAPK) signalling pathway transduces signals that cause an alteration in the ongoing metabolic pathways and modifies gene expression patterns; thus, influencing cellular behaviour. ERK/MAPK signalling is essential for the proper development of the nervous system from neural progenitor cells derived from the embryonic mesoderm. Several signalling molecules that regulate the well-coordinated process of neurodevelopment transduce developmental information through the ERK/MAPK signalling pathway. The ERK/MAPK is a potential novel therapeutic target in several neurodevelopmental disorders, however, despite years of study, there is still significant uncertainty about the exact mechanism by which the ERK/MAPK signalling pathway elicits specific responses in neurodevelopment. Here, we will review the evidence highlighting the role of ERK/MAPK signalling in neurodevelopment. We will also discuss the structural implication and behavioural deficits associated with perturbed ERK/MAPK signalling pathway in cortical development, whilst examining its contribution to the neuropathology of several neurodevelopmental disorders, such as Autism Spectrum Disorder, Schizophrenia, Fragile X, and Attention Deficit Hyperactive Disorder.

Neurovascular dysfunctions in hypertensive disorders of pregnancy.

Hypertensive disorders in pregnancy pose a huge challenge to the socioeconomic stability of a community; being a major cause of maternal and neonatal morbidity and mortality during delivery. Although there have been recent improvements in management strategies, still, the diversified nature of the underlying pathogenesis undermines their effectiveness. Generally, these disorders are categorized into two; hypertensive disorders of pregnancy with proteinuria (pre-eclampsia and eclampsia) and hypertensive disorders of pregnancy without proteinuria (gestational and chronic hypertension). Each of these conditions may present with unique characteristics that have interwoven symptoms. However, the tendency of occurrence heightens in the presence of any pre-existing life-threatening condition(s), environmental, and/or other genetic factors. Investigations into the cerebrovascular system demonstrate changes in the histoarchitectural organization of neurons, the proliferation of glial cells with an associated increase in inflammatory cytokines. These are oxidative stress indicators which impose a deteriorating impact on the structures that form the neurovascular unit and the blood-brain barrier (BBB). Such a pathologic state distorts the homeostatic supply of blood into the brain, and enhances the permeability of toxins/pathogens through a process called hyperperfusion at the BBB. Furthermore, a notable aspect of the pathogenesis of hypertensive disorders of pregnancy is endothelial dysfunction aggravated when signaling of the vasoprotective molecule, nitric oxide, amongst other neurotransmitter regulatory activities are impaired. This review aims to discuss the alterations in cerebrovascular regulation that determine the incidence of hypertension in pregnancy.

The aging brain: impact of heavy metal neurotoxicity.

The aging process is accompanied by critical changes in cellular and molecular functions, which upset the homeostatic balance in the central nervous system. Accumulation of metals renders the brain susceptible to neurotoxic insults by mechanisms such as mitochondrial dysfunction, neuronal calcium-ion dyshomeostasis, buildup of damaged molecules, compromised DNA repair, reduction in neurogenesis, and impaired energy metabolism. These hallmarks have been identified to be responsible for neuronal injuries, resulting in several neurological disorders. Various studies have shown solid associations between metal accumulation, abnormal protein expressions, and pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic lateral sclerosis. This review highlights metals (such as manganese, zinc, iron, copper, and nickel) for their accumulation, and consequences in the development of neurological disorders, in relation to the aging brain.

Epigenetic influence of environmentally neurotoxic metals.

Continuous globalization and industrialization have ensured metals are an increasing aspect of daily life. Their usefulness in manufacturing has made them vital to national commerce, security and global economy. However, excess exposure to metals, particularly as a result of environmental contamination or occupational exposures, has been detrimental to overall health. Excess exposure to several metals is considered environmental risk in the aetiology of several neurological and neurodegenerative diseases. Metal-induced neurotoxicity has been a major health concern globally with intensive research to unravel the mechanisms associated with it. Recently, greater focus has been directed at epigenetics to better characterize the underlying mechanisms of metal-induced neurotoxicity. Epigenetic changes are those modifications on the DNA that can turn genes on or off without altering the DNA sequence. This review discusses how epigenetic changes such as DNA methylation, post translational histone modification and noncoding RNA-mediated gene silencing mediate the neurotoxic effects of several metals, focusing on manganese, arsenic, nickel, cadmium, lead, and mercury.

The effects of manganese overexposure on brain health.

Manganese (Mn) is the twelfth most abundant element on the earth and an essential metal to human health. Mn is present at low concentrations in a variety of dietary sources, which provides adequate Mn content to sustain support various physiological processes in the human body. However, with the rise of Mn utility in a variety of industries, there is an increased risk of overexposure to this transition metal, which can have neurotoxic consequences. This risk includes occupational exposure of Mn to workers as well as overall increased Mn pollution affecting the general public. Here, we review exposure due to air pollution and inhalation in industrial settings; we also delve into the toxic effects of manganese on the brain such as oxidative stress, inflammatory response and transporter dysregulation. Additionally, we summarize current understandings underlying the mechanisms of Mn toxicity.

Oligodendrocytes Death Induced Sensorimotor and Cognitive Deficit in N-nitro-L-arginine methyl Rat Model of Pre-eclampsia.

Pre-eclampsia (PE) is a pregnancy complicated syndrome that affects multiple organs including the brain that continue post- delivery in both mother and the offspring. We evaluated the expression of oligodendrocytes in the brain of PE rat model through development as well as the cognitive changes and other behavioural modifications that may occur later in the life of offspring of PE-like rat model. Pregnant rats divided into early-onset and late-onset groups were administered with N-nitro- L-arginine methyl (L-NAME) through drinking water at gestational days (GD) 8-17. Rats were allowed free access to water throughout the pregnancy. At GD 19, post-natal day (PND) 1 and 60, rats were sacrificed and brain excised for further analysis. The offspring were subjected to behavioural studies for cognitive and sensorimotor impairments before sacrificed at PND 60. Results showed significant down-regulation in the expression of OLIG2 in PE at GD 19 brain which persists till PND 60. Likewise, there was a significant increase in the latency to locate the platform in Morris water maze, time to traverse the balance beam and reduced hanging time on the wire test between the control and the PE treated. PE could lead to impaired neuronal signalling through demyelination which may contributes significantly to long-term sensorimotor and cognitive deficit.

Changes in the structure and function of the brain years after Pre-eclampsia.

Pre-eclampsia (PE) is a pregnancy specific syndrome that affects multiple organs including the brain. PE resolves after delivery of the placenta. Nonetheless, PE is a predisposing factor for cardiovascular disorders and hypertension later in life. These conditions are associated with a cognitive decline and dementia later in life. Studies have suggested that there may be long term pathological changes within the brain of the woman after PE/eclampsia and PE may be a risk marker for early cerebrovascular impairment. The aim of this review is to provide an insight into the possible long-term effect of PE and eclampsia on the brain structure and function with the probability of PE being a risk factor for neurodegenerative development. Long term effects of PE include cognitive impairment such as memory loss, attention deficit and motor speed impairment. Also, the pathology of the brain seems to be much affected later in life in women with history of PE/eclampsia. Certain changes in the structure and function of the brain observed among women with history of PE/eclampsia are similar to neurological disease like Alzheimer's disease (AD) and dementia.