Attenuation of Vanadium-Induced Neurotoxicity in Rat Hippocampal Slices (In Vitro) and Mice (In Vivo) by ZA-II-05, a Novel NMDA-Receptor Antagonist.

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.

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.

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.

Neurobehavioural and Histological Study of the Effects of Low-Dose and High-Dose Vanadium in Brain, Liver and Kidney of Mice.

Vanadium is a ubiquitous transition metal that has been generating contrasting research interest. Therapeutically, vanadium possess antidiabetic, antitumor, antiparasitic and even neuroprotective activities. On the flip side, vanadium has been reported to cause multisystemic toxicities with a strong predilection for the nervous system. Despite several reports on potential benefits of low-dose vanadium (LDV) and toxic effects of high-dose vanadium (HDV), there are no comparative studies done thus far. This study therefore explored the comparative effects of LDV and HDV exposure in mice during postnatal development. A total of nine (9) nursing mice were used in this study; with three nursing mice and their pups (n = 12 pups per group) randomly assigned to each of the three test groups. The nursing dam were given intraperitoneal (i.p) injection of vanadium at 0.15mg/kg and 3mg/kg for LDV and HDV respectively, and subseqently to the pups from postnatal day (PND) 15 till sacrifice on PND 90. We discovered that neurodevelopmental motor function test of mice-pups exposed to LDV here showed improved motor development, muscular strength and memory capacities whereas HDV led to motor function impairment, reduced muscular strength and memory capacities.  LDV-exposed mice showed mild histological lesions in cerebral cortex whereas high-dose showed distinct histological lesions in different parts of the brain ranging from cerebellar Purkinje neuronal pathology (central chromatolysis), pyramidal neuronal loss in CA1 region, architectural distortion as well as fewer neurons in olfactory bulb. We saw mild lesions with LDV in both liver and kidney, however, with HDV exposure, there was diffuse hepatocellular vacuolar degeneration and congestion of blood vessels in liver, shrinkage of renal glomerulus and degenerated epithelial cells of kidney. Conclusively, beneficial effect of vanadium is proven as it facilitated body weight gain which translate in organ weight at low-dose, while high-dose caused decreased neurobehaviour and histological lesions.

Ameliorative effects of the aqueous extract of Khaya anthotheca (Welw.) C.DC (Meliaceae) in vanadium induced anxiety, memory loss and pathologies in the brain and ovary of mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical enquiries have revealed that Khaya anthotheca (Welw.) C.DC (Meliaceae) has anxiolytic properties and is used to alleviate vaginal dryness in postmenopausal women in Cameroon. The aim of this study was to evaluate the ameliorative effects of the aqueous extract of K. anthotheca in vanadium induced anxiety, memory loss and pathologies in the brain and ovary of mice. MATERIAL AND METHODS: Forty neonatal female mice were used in this study. All animals received vanadium (3 mg/kg BW/72 h, by lactation and i.p.) for 20 weeks except the Control group. At 16 weeks old, mice were divided into 5 groups (n = 8): Control group received distilled water; V-group received vanadium (V) (3 mg/kg BW every 72 h i.p.), V + Vit E group received vitamin E (500 mg/kg BW/72 h) and vanadium (V) (3 mg/kg BW/72 h i.p, simultaneously). V + KA 125 and V + KA 250 groups received K. anthotheca extract at the doses of 125 and 250 mg/kg BW/day respectively and vanadium (V) (3 mg/kg BW/72 h i.p, simultaneously).The treatment was done per os at 10 mL/kg of volume of administration for 4 weeks. To evalute anxiolytic effects and spatial working memory improved by the extract in mice, the elevated open space test and Y maze test were used respectively. After sacrifice, brains were harvested and pathologies were assessed using cresyl violet stainning and immunohistochemistry (GFAP, Iba-1 and MBP), while pathologies in the ovaries were assessed using immunohistochemistry (Collagen type 1) and H&E stainning. RESULTS: Results in the three sessions of elevated open space test showed that vanadium exposure resulted in a significant (p < 0.05; p < 0.01) increase of the latency of first entry in the slopes and a significant (p < 0.05; p < 0.01; p < 0.001) decrease of the time spent and number of entries in the slopes however, Khaya anthotheca treatment induced a significant (p < 0.05; p < 0.01) decrease of the latency of first entry in the slopes and a significant (p < 0.05; p < 0.01) increase of the time spent and number of entries in the slopes. In the Y maze test, vanadium exposure resulted in a significant decrease (p < 0.01) in the percentage of correct alternation, K. anthotheca extract at the dose of 250 mg/kg BW however induced a significant (p < 0.05) increase of this percentage of correct spontaneous alternation. In the brain, degeneration induced by vanadium exposure was marked by an increase of GFAP-immunoreactive cells, microgliosis and demyelination. The treatment with Khaya anthotheca extract at the dose of 250 mg/kg BW resulted in the preservation of cellular integrity in the same anatomical regions with reduced astroglial and microglial activation and prevented demyelination. In addition, vanadium exposure decreased Collagen type 1 expression in the ovaries and induced a deterioration of tertiary follicle. Khaya anthotheca treatment at the dose of 250 mg/kg BW induced an increase of expression of Collagen type 1 and alleviated deterioration of the microarchitecture of tertiary follicle induced by vanadium. CONCLUSION: These effects induced by K. anthotheca extract could justify the traditional use of this plant in Cameroonian traditional medicine to manage anxiety. Therefore, to minimise vanadium induced toxicity, the plant should be given more emphasis as a candidate in developing a modern phytodrug.

The Pathopharmacological Interplay between Vanadium and Iron in Parkinson's Disease Models.

Parkinson's disease (PD) pathology is characterised by distinct types of cellular defects, notably associated with oxidative damage and mitochondria dysfunction, leading to the selective loss of dopaminergic neurons in the brain's substantia nigra pars compacta (SNpc). Exposure to some environmental toxicants and heavy metals has been associated with PD pathogenesis. Raised iron levels have also been consistently observed in the nigrostriatal pathway of PD cases. This study explored, for the first time, the effects of an exogenous environmental heavy metal (vanadium) and its interaction with iron, focusing on the subtoxic effects of these metals on PD-like oxidative stress phenotypes in Catecholaminergic a-differentiated (CAD) cells and PTEN-induced kinase 1 (PINK-1)B9Drosophila melanogaster models of PD. We found that undifferentiated CAD cells were more susceptible to vanadium exposure than differentiated cells, and this susceptibility was modulated by iron. In PINK-1 flies, the exposure to chronic low doses of vanadium exacerbated the existing motor deficits, reduced survival, and increased the production of reactive oxygen species (ROS). Both Aloysia citrodora Paláu, a natural iron chelator, and Deferoxamine Mesylate (DFO), a synthetic iron chelator, significantly protected against the PD-like phenotypes in both models. These results favour the case for iron-chelation therapy as a viable option for the symptomatic treatment of PD.