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Calbindin staining of the cerebellar cortex region; Arrows indicate presence of dendrites in Control (a and b) and compound C treated mice (d) compared with vanadium-treated mice (c) which shows loss of Purkinje cells and apical dendrites, greater percentage of cytoplasmic vacuolations and lack of vitality (˄). Bar chart (e) shows viable Purkinje cells in the cerebellar cortex were significantly less in the vanadium-treated group when compared with control and compound C treated groups. Magnification ×400, scale bar, 20 μm. *p < 0.05; (one-way ANOVA, followed by Tukey comparison test)
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Various NMDA-receptor antagonists have been investigated for their
therapeutic potential in Alzheimer’s disease with memantine shown to be safe
and with relative efficacy. There is, however, need to develop novel drugs to
counter tolerance and with better efficacy in ameliorating neurodegeneration. We
have shown neurodegeneration in different model...
Citations
... This finding provides further evidence of disrupted calcium balance in the presence of vanadium exposure. Our previous study also observed a similar trend using calbindin, a calcium-binding protein [27], supporting the presence of calcium dyshomeostasis. The observed phenomenon (Figure 1) can be attributed to the perturbation of calcium signaling induced by vanadium, leading to the disturbance of regular neuronal communication and functioning. ...
... It is possible that ZA-II-05 prevents the penetration and actions of vanadium, although the exact mechanism requires further investigation. Notably, the demyelinating effect of vanadium and its mitigation through the use of ZA-II-05 is consistent with previous findings [27]. ...
... In the vanadiumtreated group, we observed microglial activation in the CA 3 region of the hippocampus, choroid plexus, and the third ventricle of the brain. Environmental toxicants are known to readily trigger their activation [27]. The activated microglia displayed cellular hypertrophy, and their processes exhibited a bushy appearance. ...
Exposure to heavy metals, such as vanadium, poses an ongoing environmental and health threat, heightening the risk of neurodegenerative disorders. While several compounds have shown promise in mitigating vanadium toxicity, their efficacy is limited. Effective strategies involve targeting specific subunits of the NMDA receptor, a glutamate receptor linked to neurodegenerative conditions. The potential neuroprotective effects of ZA-II-05, an NMDA receptor antagonist, against vanadium induced neurotoxicity were explored in this study. Organotypic rat hippocampal slices, and live mice, were used as models to comprehensively evaluate the compound’s impact. Targeted in vivo fluorescence analyses of the hippocampal slices using propidium iodide as a marker for cell death was utilized. The in vivo study involved five dams, each with eight pups, which were randomly
assigned to five experimental groups (n = 8 pups). After administering treatments intraperitoneally over six months, various brain regions were assessed for neuropathologies using different immunohistochemical markers. High fluorescence intensity was observed in the hippocampal slices treated with vanadium, signifying cell death. Vanadium-exposed mice exhibited demyelination, microgliosis,
and neuronal cell loss. Significantly, treatment with ZA-II-05 resulted in reduced cellular death in the rat hippocampal slices and preserved cellular integrity and morphological architecture in different anatomical regions, suggesting its potential in countering vanadium-induced neurotoxicity.
Keywords: Alzheimer’s disease; vanadium; NMDA-receptor antagonist; neurotoxicity; hippocampus
... Though the biological functions of vanadium were well documented, its toxicity was also seen in animal studies [80,81]. The clinical study revealed that the consumption of vanadium at 125 mg/day was safe for adults [82]. ...
Vanadium is a well-known essential trace element, which usually exists in oxidation states in the form of a vanadate cation intracellularly. The pharmacological study of vanadium began with the discovery of its unexpected inhibitory effect on ATPase. Thereafter, its protective effects on β cells and its ability in glucose metabolism regulation were observed from the vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s disease (AD) is the most common dementia disease in elderly people. However, there are still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which is characterized by senile plaques composed of the amyloid-beta (Aβ) protein in the parenchyma of the brain and the neurofibrillary tangles (NFTs), which are derived from the hyperphosphorylated tau protein in the neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the impaired insulin signaling in the brain. In this review, we summarize the advances in applicating the vanadium compound to AD treatment in experimental research and point out the limitations of the current study using vanadium compounds in AD treatment. We hope this will help future studies in this field.
... Though the biological functions of vanadium were well documented, the toxicity was also seen in animal studies [12,13]. Clinical study revealed that the consumption of vanadium at 125 mg/day 2 was safe for adults [14]. ...
... Aβ: amyloid-beta AD: Alzheimer's disease ADAM10: a disintegrin and metalloproteinase 10 AGD: argyrophilic grain disease AICD: APP intracellular domain APOE: apolipoprotein E APP: amyloid precursor protein BEOV: bis(2-ethyl-3-hydroxy-4-pyronato) oxovanadium (IV) BMOV: bis(maltolato) oxovanadium(IV) CAA: cerebral amyloid angiopathy CBD: corticobasal degeneration CDK5: cyclin-dependent kinase 5 COX2: cyclooxygenase-2 CTE: chronic traumatic encephalopathy CTF-83: C-terminal fragment CNS: central nervous system Drp1: dynamin-related GTPase FAD: familial AD FTDP-17: frontotemporal dementia with Parkinsonism linked to chromosome 17 GIP: glucose-dependent insulinotropic polypeptide GLUT4: glucose transporter 4 GSIS: glucose-stimulated insulin secretion GSK-3β: 3glycogen synthase kinase -3 IDE: insulin degrading enzyme IGF: insulin-like growth factor iNOS: inducible nitric oxide synthase IR: insulin receptor IRS2: insulin receptor substrate LTP: long-term potentiation MFN: mitofusion NFTs: neurofibrillary tangles Nrf2: nuclear factor-erythroid-2-related factor 2 PGC-1α: proliferator activated receptor gamma coactivator 1 α PI3K: phosphatidylinositol-3-kinase PiD: Pick's disease 12 ...
Vanadium is a well-known essential trace element, which usually exists in oxidation states in form of vanadate cation intracellularly. The pharmacological study of vanadium begins at the discovery of its unexpected inhibitory effect on ATPase. Thereafter, the protective effects on cells and the abilities in glucose metabolism regulation were observed from vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s dis-ease (AD) is the most common dementia disease in elderly people. However, there is still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which are characterized by the senile plaques composed by amyloid-beta (Aβ) protein in the parenchyma of brain and the neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau protein in neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes, because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the im-paired insulin signaling in brain. In this review, we summarized the advance of applicating vanadium compound on AD treatment in experimental research and pointed out the limitation of the current study on using vanadium compounds in AD treatment. We hope it will help the future study in this field.
... NMDAR antagonists can alleviate hyperalgesia and allodynia neuropathic pain caused by nerve damage and diabetic neuropathy in animal models 9 . Different NMDAR antagonists are used to treat neurodegeneration in mice with vanadium-induced neurotoxicity 10 . In addition, amantadine, an NMDAR antagonist administered to rats, can restore spinal cord damage by preventing oxidative stress 11 . ...
Objective:
The study aimed to examine the effects of two drugs, an acetylcholinesterase inhibitor (AChEI) and an N-methyl-D-aspartate receptor (NMDAR) antagonist, on degenerated annulus fibrosus (AF) and nucleus pulposus (NP) cells and the extracellular matrix (ECM) structure in vitro.
Patients and methods:
Tissue samples were obtained from patients with intervertebral disc herniation (four males and four females; classified as Pfirmann stage IV) and used to prepare cell cultures. Untreated cell culture samples served as the control group. Study group samples were treated with donepezil, memantine or a combination of the two drugs. Cell viability, toxicity and proliferation were evaluated in all groups. Western blotting was used to examine changes in protein expression of signal transducer and activator of transcription 3 (STAT3), phospho-STAT3 (ser727), hypoxia-inducible factor (HIF)-1 alpha (HIF-1α) and nucleotide-binding oligomerisation domain (NOD) leucine-rich repeat (LRR)-containing proteins (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. The alpha significance value was < 0.05.
Results:
Analysis of the microscopy and commercial kit results revealed that cell proliferation was suppressed, and no cell death was observed. The protein expression levels of NLRP3, STAT3, ser727 and HIF-1α were lower in the samples treated with donepezil and memantine at 72 h (p < 0.05). The protein expression levels of NLRP3, STAT3, ser727 and HIF-1α were higher in the samples treated with the combination of donepezil and memantine (p < 0.05).
Conclusions:
The combined administration of memantine a NMDAR antagonist which can prevent neurodegeneration and donepezil an AChEI used for pain relief increased the protein expression levels in the anabolic pathway. However, it did not reduce the protein expression levels in the catabolic pathway. Therefore, further studies are needed to provide extensive insight into whether it may be among the potential targets for the therapy of intervertebral disc (IVD) diseases.
... In addition, it was found that elevated vanadium uptake could affect cholesterol and triglyceride metabolism, and stimulate hepatic glucose oxidation and glycogen synthesis [27]. However, the toxicity of vanadium was also observed in animal experiments [28,29], though the biological effects may be different dependent on the species of vanadium compounds formed in the biological media [30]. Rats would all die when they were treated with vanadyl sulfate at levels greater than 2 mM V kg −1 body weight [31]. ...
Alzheimer’s disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aβ) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have been proposed, including the amyloid cascade hypothesis, the oxidative stress hypothesis, the inflammatory hypothesis, the cholinergic hypothesis, et al. In the meantime, great efforts had been made in developing effective drugs for AD. However, the clinical efficacy of the drugs that were approved by the US Food and Drug Association (FDA) to date were determined only mild/moderate. We recently adopted a vanadium compound bis(ethylmaltolato)-oxidovanadium (IV) (BEOV), which was originally used for curing diabetes mellitus (DM), to treat AD in a mouse model. It was shown that BEOV effectively reduced the Aβ level, ameliorated the inflammation in brains of the AD mice, and improved the spatial learning and memory activities of the AD mice. These finding encouraged us to further examine the mechanisms underlying the therapeutic effects of BEOV in AD. In this review, we summarized the achievement of vanadium compounds in medical studies and investigated the prospect of BEOV in AD and DM treatment.
... V crosses the blood-brain barrier [7], and its compounds can induce neurologic alterations through different routes of administration [3,11]. It has been reported that V-exposed lactating rat pups developed neurological deficits [35]; other authors described neurological alterations and increased brain V concentration after sodium metavanadate intraperitoneal administration [36][37][38]. Also, our group [7, 8] reported neuroinflammation in the brain of mice that inhale V 2 O 5. We found a seven-fold peak increase in V brain concentration after one week of inhalation and remained constant (0.10-0.12 mg/g dry weight tissue) during eight weeks of V 2 O 5 inhalation. ...
Vanadium (V), a widely distributed transition metal, has been considered toxic, which depends on the valence of the compound. V pentoxide (V2O5) is considered the most harmful. Its long-term exposure produces neurotoxicity. Mice exposed to inhaled V2O5 displayed less tubulin+ in testicular cells and dendritic spines loss, cell death, and CA1 neuropil modifications, considered as the result of V interaction with the cytoskeleton, which made us suppose that V2O5 inhalation could initiate CA1 cell alterations comparable to what happen in the brains of Alzheimer disease (AD) patients. This study intends to demonstrate pyramidal CA1 cytoskeletal changes in rats which inhaled V2O5. Twenty rats were exposed to V2O5 0.02 M one hour, three times a week for several months. Our findings showed that V2O5-exposed rats had cell death that reached 56,57% after six months; we also observed collapsed strong argyrophilic nuclei and characteristic flame-shaped somas in all V2O5-exposed animals hippocampus CA1 compared to controls. We also found somatodendritic deformations. Neurite’s cytoskeleton exhibited visible thickening and nodosities and prominent dendritic spine loss. Our results demonstrate that V2O5 induces AD-like cell death with evident cytoskeletal and synaptic alterations.
... Serial transverse and longitudinal sections of 5-µm thickness were prepared by using a HM330 Micron Microtome. For general histological examination, paraffin representative sections were stained by Hematoxylin and Eosin and Cresyl Violet as depicted by Suvarna et al (2013) and Ladagu et al (2020). ...
The striped owl (Asio clamator) is unique with its brownish white facial disc and they are found in the north eastern part of Nigeria. Little is known in the literature on the basic neuroanatomy of this species. This study focuses on the histology and glial expression of some brain regions of the striped owl. Five owls were obtained in the wild, and their brains were routinely prepared for Haematoxylin and Eosin, and Cresyl violet staining. Immunostaining was done with anti-Calbindin, anti MBP, anti-GFAP, and anti-Iba-1 antibodies; for the expression of cerebellar Purkinje cells and white matter, cerebral astrocytes and microglia cells respectively. These were qualitatively described. We found that the hippocampal formation of the striped owl, though unique, is very similar to what is seen in mammals. The cerebellar cortex is convoluted, has a single layer of Purkinje cells with profuse dendritic arborization, a distinct external granular cell layer, and a prominent stem of white matter were seen in this study. The astrocytic population in cerebral gray is similar, though lacking in many processes as is typical in protoplasmic astrocytes, while the microglia were not strongly stained. The few stained microglia cells did not, however, show any features of activation. The striped owl's brain reveals some conserved aspects of cellular neuroanatomy in both the avian and mammals that are typical in these species. More work is however needed particularly in age related differences in these structures. This is perhaps the first report of Calbindin immunostaining in the brain of the striped owl.
N-methyl-D-aspartate receptors (NMDARs) are ion channels that respond to the neurotransmitter glutamate, playing a crucial role in the permeability of calcium ions and excitatory neurotransmission in the central nervous system (CNS). Composed of various subunits, NMDARs are predominantly formed by two obligatory GluN1 subunits (with eight splice variants) along with regulatory subunits GluN2 (GluN2A-2D) and GluN3 (GluN3A-B). They are widely distributed throughout the CNS and are involved in essential functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. The presence of GluN2A and GluN2B subunits is particularly important for cognitive processes and has been strongly implicated in neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease. Understanding the roles of GluN2A and GluN2B NMDARs in neuropathologies provides valuable insights into the underlying causes and complexities of major nervous system disorders. This knowledge is vital for the development of selective antagonists targeting GluN2A and GluN2B subunits using pharmacological and molecular methods. Such antagonists represent a promising class of NMDA receptor inhibitors that have the potential to be developed into neuroprotective drugs with optimal therapeutic profiles.
Environmental pollution with vanadium may pose neurotoxicity threats to known unique neural attributes (cognition and olfaction) of the African giant rat (AGR). This rodent lives within the same ecological zones with the human populace thus, experimental investigations on the effect of vanadium on this rodent may mirror latent epidemiological scenario on the human populace. This work was designed to evaluate the neurotoxic effect of vanadium on the hippocampal neuronal infrastructure and circuitry, and provide cellular correlates to its notable pathologies in the AGR. Adult male AGRs were dosed daily with 3mg/kg body sodium metavanadate for 14days and harvested brains were processed for histology Using Nissl and Golgi staining techniques with stereological analysis. we demonstrated the effect of vanadium on AGR neuronal architecture of the hippocampal trisynaptic loop as a probable cellular mechanism of vanadium-induced memory deficits. Specifically, the most notable pathologies were seen in the dentate gyrus and CA3 with significant decrease in neuronal density, disruption of the cytoarchitecture, and loss of dendritic arborizations and axonal extensions. while hippocampal subfields CA2 and CA4 show region-specific resistance to the vanadium-induced neurotoxicity. The selective vulnerability to the vanadium-induced neurotoxicity is adduced. Given the unique neural attributes of the AGR and their translational benefits, as sniff rats it then becomes expedient to note the impact of environmental pollution (in this case vanadium) on their performance index. It is also proposed that this indigenous rodent may be a suitable model for evaluating memory pathologies in ecological studies of neurotoxicities.
Atherosclerosis is a chronic cardiovascular disease and contributes to pathogenesis of most myocardial infarction and ischemic stroke. Additionally, N-methyl-d-aspartate (NMDA) receptor plays a crucial role in myocardial infarction and ischemic strokes. The aim of our study was to investigate the underlying mechanisms of memantine (MEM), the blocker of NMDA receptors, in the development of atherosclerosis. In our study, human umbilical vascular endothelial cells (HUVECs) were stimulated with low-density lipoprotein (ox-LDL) to establish an atherosclerotic cell model. Cell Counting Kit-8 (CCK-8) assay and TUNEL staining were performed to detect the cell activity and apoptosis of HUVECs, respectively. The levels of inflammatory cytokines and malondialdehyde and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and caspase-1 were quantified with commercial assay kits. Finally, qRT-PCR assay and western blot analysis were carried out to determine the mRNA and protein expressions of inflammation-related genes in HUVECs. The results of the present study suggested that ox-LDL stimulation induced decreased viability of HUVECs, excessive inflammation, and oxidative stress, while these effects were counteracted by MEM treatment. Interestingly, MEM triggered the activation of BDNF/TrkB signaling pathway in HUVECs, and K252a, the inhibitor of the BDNF/TrkB pathway, abolished the suppressive effect of MEM on ox-LDL-induced inflammation, oxidative stress, and apoptosis in HUVECs. Overall, MEM attenuated ox-LDL-induced inflammation, oxidative stress, and apoptosis via activation of BDNF/TrkB signaling pathway in HUVECs, indicating that MEM may be defined as a novel and effective agent for atherosclerosis treatment.
