Cajanus cajan (L) Millsp seeds extract prevents rotenone-induced motor- and non-motor features of Parkinson disease in mice: Insight into mechanisms of neuroprotection.

ETHNOPHARMACOLOGICAL RELEVANCE: Cajanus cajan (L) Millsp (Fabaceae) seed decoction is used by traditional healers in Nigeria as nerve tonic, hence, could be beneficial in the treatment of Parkinson's disease (PD), a progressive and debilitating neurodegenerative disease that imposes great burden on the healthcare system globally. AIM OF THE STUDY: This study aimed at investigating the neuroprotective effect of ethanol seed extract of Cajanus cajan (CC) in the treatment of rotenone-induced motor symptoms and non-motor symptoms associated with PD. MATERIALS AND METHODS: To assess the protective action of CC on rotenone-induced motor- and non-motor symptoms of PD, mice were first pretreated with CC (50, 100 or 200 mg/kg, p.o.) an hour before oral administration of rotenone (1 mg/kg, p.o, 0.5% in carboxyl-methylcellulose) for 28 consecutive days and weekly behavioural tests including motor assessment (open field test (OFT), rotarod, pole and cylinder tests) and non-motor assessment (novel object recognition (NOR), Y-maze test (YM), forced swim and tail suspension, gastric emptying and intestinal fluid accumulation tests) were carried out. The animals were euthanized on day 28 followed by the collection of brain for assessment of oxidative stress, inflammatory markers and immunohistochemical analysis of the striatum (STR) and substantia nigra (SN). Phytochemicals earlier isolated from CC were docked with protein targets linked with PD pathology such as; catechol-O-methyltransferase (COMT), tyrosine hydroxylase (TH) and Leucine rich receptor kinase (LRRK). RESULTS: this study showed that CC significantly reduced rotenone-induced spontaneous motor impairment in OFT, pole, cylinder and rotarod tests in mice as well as significant improvement in non-motor features (significant reversal of rotenone-induced deficits discrimination index and spontaneous alternation behaviour in NORT and YM test, respectively, reduction in immobility time in forced swim/tail suspension test, gastrointestinal disturbance in intestinal transit time in mice. Moreso, rotenone-induced neurodegeneration, oxidative stress and neuroinflammation were significantly attenuated by CC administration. In addition, docking analysis showed significant binding affinity of CC phytochemicals with COMT, TH and LRRK2 receptors. CONCLUSION: Cajanus cajan seeds extract prevented both motor and non-motor features of Parkinson disease in mice through its antioxidant and anti-inflammatory effects. Hence, could be a potential phytotherapeutic adjunct in the management of Parkinson disease.

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.

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.