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.

Clofibrate, a PPAR-α agonist, abrogates sodium fluoride-induced neuroinflammation, oxidative stress, and motor incoordination via modulation of GFAP/Iba-1/anti-calbindin signaling pathways.

Fluoride is an environmental contaminant that is ubiquitously present in air, water, and soil. It is commonly added in minute quantity to drinking water, toothpaste, and mouth rinses to prevent tooth decay. Epidemiological findings have demonstrated that exposure to fluoride induced neurodevelopmental toxicity, developmental neurotoxicity, and motor disorders. The neuroprotective effect of clofibrate, a peroxisome proliferator-activated receptor alpha agonist, was investigated in the present study. Forty male Wistar rats were used for this study and randomly grouped into 10 rats per group as control, sodium fluoride (NaF) alone (300 ppm), NaF plus clofibrate (250 mg/kg), and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. NaF was administered in drinking water while clofibrate and lisinopril were administered by oral gavage. Markers of neuronal inflammation and oxidative stress, acetylcholinesterase activity, and neurobehavioral (hanging wire and open field) tests were performed. Immunohistochemistry was performed on brain tissues, and they were probed with glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and cerebellar Ca2+ -binding protein calbindin-D28k. The results showed that NaF significantly increased of oxidative stress and neuroinflammation and inhibited AChE activity. Immunostaining showed reactive astrocytes, microgliosis, loss of dendritic spines, and arborization in Purkinje cells in rats administered only NaF. Neurobehavioral results showed that cotreatment of NaF with clofibrate improved muscular strength and locomotion, reduced anxiety, and significantly reduced astrocytic count. Overall, cotreatment of NaF with either clofibrate or lisinopril showed neuroprotective effects by mitigating neuronal inflammation and oxidative and motor incoordination. Hence, clofibrate could be seen as a novel drug candidate against neurodegeneration and motor disorders.

Brain Metal Distribution and Neuro-Inflammatory Profiles after Chronic Vanadium Administration and Withdrawal in Mice.

Vanadium is a potentially toxic environmental pollutant and induces oxidative damage in biological systems including the central nervous system (CNS). Its deposition in brain tissue may be involved in the pathogenesis of certain neurological disorders which after prolonged exposure can culminate into more severe pathology. Most studies on vanadium neurotoxicity have been done after acute exposure but in reality some populations are exposed for a lifetime. This work was designed to ascertain neurodegenerative consequences of chronic vanadium administration and to investigate the progressive changes in the brain after withdrawal from vanadium treatment. A total of 85 male BALB/c mice were used for the experiment and divided into three major groups of vanadium treated (intraperitoneally (i.p.) injected with 3 mg/kg body weight of sodium metavanadate and sacrificed every 3 months till 18 months); matched controls; and animals that were exposed to vanadium for 3 months and thereafter the metal was withdrawn. Brain tissues were obtained after animal sacrifice. Sagittal cut sections of paraffin embedded tissue (5 µm) were analyzed by the Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to show the absorption and distribution of vanadium metal. Also, Haematoxylin and Eosin (H&E) staining of brain sections, and immunohistochemistry for Microglia (Iba-1), Astrocytes (GFAP), Neurons (Neu-N) and Neu-N + 4',6-diamidine-2'-pheynylindole dihydrochloride (Dapi) Immunofluorescent labeling were observed for morphological and morphometric parameters. The LA-ICP-MS results showed progressive increase in vanadium uptake with time in different brain regions with prediction for regions like the olfactory bulb, brain stem and cerebellum. The withdrawal brains still show presence of vanadium metal in the brain slightly more than the controls. There were morphological alterations (of the layering profile, nuclear shrinkage) in the prefrontal cortex, cellular degeneration (loss of dendritic arborization) and cell death in the Hippocampal CA1 pyramidal cells and Purkinje cells of the cerebellum, including astrocytic and microglial activation in vanadium exposed brains which were all attenuated in the withdrawal group. With exposure into old age, the evident neuropathology was microgliosis, while progressive astrogliosis became more attenuated. We have shown that chronic administration of vanadium over a lifetime in mice resulted in metal accumulation which showed regional variabilities with time. The metal profile and pathological effects were not completely eliminated from the brain even after a long time withdrawal from vanadium metal.