Chandamarutha Chenduram, an Indian traditional Siddha preparation attenuated the neuronal degeneration in ischemic mice through ameliorating cytokines and oxy-radicals mediated EAAT-2 dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Chandamarutha Chenduram (CC), an Indian traditional Siddha preparation officially recorded in the Siddha formulary of India and its composition are widely used in the Siddha practice of neurological disorders like stroke/paralysis in India. However, the scientific validation and mechanistic evidence is lacking and yet to be elucidated. AIM OF THE STUDY: To establish the scientific evidences and to explore the possible neuroprotective mechanism of CC in cerebral ischemia. MATERIALS AND METHODS: Chemical standardization of the CC was performed using atomic absorption spectroscopy and gravimetric analysis. Acute toxicity study for CC in mice was performed in accordance with OECD 423 guidelines. CC (5 mg/kg) and CC (10 mg/kg) were investigated in bilateral common carotid occlusion (BCCAo) model in mice. After, behavioral assessments, the brain samples were collected and the hippocampus region was micro-dissected for neurotransmitter, neurobiochemicals and inflammatory cytokines estimation. The excitatory amino acid transporter-2 (EAAT-2) expressions was analyzed by RT-PCR to understand the possible molecular mechanism. In addition, hematoxylin and eosin staining of CA1 hippocampal brain region was performed to support the neuroprotective effect of CC in ischemic condition. RESULTS: Chemical standardization analysis showed that CC has acceptable range of mercury (0.82 ppm) and elemental sulphur (11% w/w). Also, other heavy metal limits were found to be less or not detectable. Toxicity study also evidenced the safety profile of CC. CC has significantly reversed the behavioral dysfunctions (p < 0.001) in global ischemic mice. Treatment with CC has attenuated the excitatory neurotransmitter glutamate, lipid peroxide, nitric oxide, cytokines (IL-1ß, TNF-α) (p < 0.001) and increased the antioxidant enzymes (SOD, CAT, GSH) and EAAT-2 expression level (p < 0.001) in ischemic brain. The hematoxylin and eosin staining in CA1 region of hippocampus also evidence the neuroprotective effect exhibited by CC. CONCLUSIONS: Treatment with CC has exhibited dose dependent effect and CC10 has shown significant protective effect in comparison to CC5 in most of the parameters studied. CC prevented further degeneration of neurons in cerebral ischemic mice through ameliorating inflammatory cytokines and oxy-radicals mediated EAAT-2 dysfunction and subsequent excitotoxicity in neurons.

Desferrioxamine and dextromethorphan combination exhibited synergistic effect and reversed the catalepsy behaviour in 6-hydroxydopamine hydroydopamine administered rats through regulating brain glutamate levels.

OBJECTIVE: To investigate the effect of desferrioxamine (DFO) and dextromethorphan (DXM) combination in animal model of Parkinson's disease (PD). METHODS: The PD was induced in rats through intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) using stereotaxic apparatus. The animals were subjected to behavioural assessments and neurobiochemicals estimation followed by immunohistochemistry staining of neuron specific enolase (NSE) in striatum. KEY FINDINGS: Desferrioxamine and DXM combination has significantly reversed the catalepsy behaviour and elevated the antioxidant enzymes (SOD, CAT, GSH) and dopamine levels. Interestingly, the level of glutamate, nitric oxide, cytokines (IL-1ß, TNF-α) and NSE expressions were found to be decreased in striatum region of 6-OHDA-administered rats. The combination of DFO and DXM has shown synergism in most of the parameters studied, when compared to per se treatment. CONCLUSIONS: The reversal of catalepsy behaviour represents the protective effect of above combination on dopamine neurons in striatum from 6-OHDA toxicity. The mechanism of DFO and DXM combination might be attributed through attenuation of glutamate-induced excitotoxicity in neurons through ameliorating the reactive oxygen species and pro-inflammatory cytokines release. Treatment with DFO and DXM combination could control the multiple events in the pathogenesis of PD.