Withaferin-A Protects the Nigral Dopamine Neuron and Recovers Motor Activity in Aged Rats.

Withaferin-A (WA) was evaluated for its neuroprotective efficacy on the dopamine (DA) neurons of the substantia nigra (SN) and striatum (ST) in aged rats. Wistar albino rats were divided into group I, young (3 months old); group II, aged (24 months old); group III, aged rats supplemented with WA (50 mg/kg bodyweight once per day for 30 days), and group IV, young rats supplemented with WA (50 mg/kg bodyweight). At the end of the experiment period, the animals were subjected to various motor behavior analyses, and were sacrificed by transcardial perfusion. The brains were dissected out and subjected to various analyses, including histological, histomorphometrical, and immunolocalization of the tyrosine hydroxylase (TH) enzyme. The data of rotarod analysis (p < 0.001) showed a significant motor impairment in aged rats (number of falls 10.2 ± 0.86) and reduction in retention time (31.23 ± 2.56 s) compared to young controls (2.41 ± 0.35 and 84.05 ± 5.15 s). The stride length was significantly reduced (p < 0.001) in aged rats (4.21 ± 0.57 and 4.38 ± 0.61 cm) when compared to young control rats (6.98 ± 0.25 and 7.13 ± 0.70 cm). The histomorphometric data of the aged animals showed a significant reduction in the neuronal diameter (p < 0.001), density (p < 0.001), and volume (p < 0.001) in the SN of aged rats when compared to young rats. Immunohistology demonstrated a marked reduction in the levels of TH enzyme in both the SN and ST of aged animals when compared to young rats. Both structural and functional impairments were reversed in the aged animals after the supplementation of WA (p < 0.001). The present study clearly indicates that WA attenuates the ageing-mediated motor degenerative changes in the SN and ST of aged rats and ascertains its neuroprotective potential.

Demethoxycurcumin ameliorates rotenone-induced toxicity in rats.

Rotenone, an environmental toxin, is used to induce neurodegeneration in both the cellular and animal model of Parkinson's disease. Demethoxycurcumin (DMC), derivative of curcumin has been reported to have antioxidant and anti-inflammatory characteristics in in vitro and in vivo PD conditions. The present study was aimed to evaluate the efficacy of DMC in the management of neurodegeneration in PD. Male Wistar rats were radomized and divided into control, rotenone, DMC +rotenone and rotenone alone treated animals. Pre-treatment with DMC one hour prior to the rotenone injection, attenuated the motor and non-motor deficits. Western blot analysis indicated that the administration of DMC to PD rats eased the protein expression of dopaminergic and apoptotic indices. These findings showed that DMC effects on ameliorating the PD symptoms induced by rotenone might be associated with the neuroprotective and antioxidant effects of this compound.

Antiapoptotic role of Agaricus blazei extract in rodent model of Parkinson's disease.

Rotenone is a pesticide that has been shown to induce the pathological symptoms of Parkinson's disease (PD) in both cellular and animal models. In this study, we investigated the protective effect of Agaricus blazei extract on rotenone-induced dopaminergic degeneration and apoptosis in mice model. A. blazei extract blocked the rotenone-mediated diminution of   dopamine transporter (DAT)  and vesicular monoamine transporter 2 (VMAT 2) expression and  the downregulation of Bcl-2 and the upregulation of Bax, caspases-3, -6, -8 and caspase-9. Present data suggest that A. blazei extract plays a crucial role in regulation of proteins expression such as DAT and VMAT2 and pro-apoptotic and anti-apoptotic in Parkinsonism. In conclusion, the present study shows that A. blazei extract act as potential neuroprotective agent in the management of Parkinsonism.

Ameliorative Effect of Withaferin A on Ageing-Mediated Impairment in the Dopamine System and Its Associated Behavior of Wistar Albino Rat.

Withaferin A (WA) was evaluated for its neuro-protective efficacy on ageing induced striatal dopamine (DA) and behavioural changes in aged rats. Wistar albino rats were divided into group I - young (3 months), Group II - aged (24 months), Group III - aged rats supplemented with WA (50 mg/kg b.w once in a day for 30 days) and Group IV - young rats supplemented with WA (50 mg/kg b.w). The HPLC assay revealed significant decline in the levels of DA and homovanillic acid (HVA) in substantia nigra (SN) and striatum (ST) of aged rat. A marked decline in motor activity of aged rat was observed through open field, beam walking and grid walking motor experiments. These results indicate that ageing reduces nigro-striatal activity as well as nigro-striatal DA levels. Interestingly, the administration of WA (50 mg\kg b.w) resulted in a substantial resurge of DA and HVA in SN and ST and a significant reversal of motor impairment in aged rats. This study is the first report that evidently determines the neuro-protective efficacy of WA on dopaminergic system of SN and ST in aged rats.

Demethoxycurcumin, a Natural Derivative of Curcumin Abrogates Rotenone-induced Dopamine Depletion and Motor Deficits by Its Antioxidative and Anti-inflammatory Properties in Parkinsonian Rats.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder (NDD) associated with the loss of dopaminergic neurons in the substantia nigra and subsequently has an effect on motor function and coordination. The pathology of PD is multifactorial, in which neuroinflammation and oxidative damage are the two of the main protagonists. OBJECTIVES: The present study aims to assess the potential antioxidant and anti-inflammatory effects of demethoxycurcumin (DMC), a natural derivative of curcumin, against rotenone-induced PD in rats. MATERIALS AND METHODS: Rats were randomized and divided into six groups: control, rotenone (0.5 mg/kg/day, intraperitoneal in sunflower oil) treated for 7 days, rotenone and DMC (5, 10, and 20 mg/kg b.w) cotreated, and DMC (20 mg/kg b.w) alone treated groups. RESULTS: Based on the dopamine concentration and biochemical estimations, the effective dose of DMC was selected and the chronic study was performed. At the end of the experimental period, behavioral studies and protein expression patterns of inflammatory markers were analyzed. Rotenone treatment led to motor dysfunctions, neurochemical deficits, and oxidative stress and enhanced expressions of inflammatory markers, whereas oral administration of DMC attenuated all the above. CONCLUSION: Even though further research is needed to prove its efficacy in clinical trial, the results of our study showed that DMC may offer a promising and new therapeutic lead for the treatment of NDDs including PD. SUMMARY: Curcumin and their derivatives have been shown to be potent neuroprotective effectDemethoxycurcumin (DMC) amolerated the rotenone induced behavioural alterationsDMC abrogated the rotenone induced dopamine deficitsDMC attenuated the rotenone induced oxidative stressDMC diminished the rotenone mediated inflammation. Abbreviations used: COX-2: Cyclooxygenase-2; DA: Dopamine; DMC: Demethoxycurcumin; DMRT: Duncan's multiple range test; GSH: Reduced glutathione; GPx: Glutathione peroxidase; IL-1 ß: Interleukin-1 ß; IL-6: Interleukin-6; iNOS: Inducible nitric oxide synthase; PD: Parkinson's disease; SN: Substantia nigra; SOD: Superoxide dismutase; TBARS: Thiobarbituric acid reactive substances; TNF-α: Tumor necrosis factor-α.

Agaricus blazei extract abrogates rotenone-induced dopamine depletion and motor deficits by its anti-oxidative and anti-inflammatory properties in Parkinsonic mice.

Neuroinflammation and oxidative damage are the two main malfactors that play an important role in the pathogenesis of experimental and clinical Parkinson's disease (PD). The current study was aimed to study the possible anti-oxidant and anti-inflammatory effects of the methanolic extract of Agaricus blazei (A. blazei) against rotenone-induced PD in mice. Male Albino mice were randomized and divided into the following groups: control, treated with rotenone (1 mg/kg/day), co-treated with rotenone and A. blazei (50, 100, and 200 mg/kg b.w.), and treated with A. blazei alone (200 mg/kg b.w.). After the end of the experimental period, behavioral studies, biochemical estimations, and protein expression patterns of inflammatory markers were studied. Rotenone treatment exhibited enhanced motor impairments, neurochemical deficits, oxidative stress, and inflammation, whereas oral administration of A. blazei extract attenuated the above-said indices. Even though further research is needed to prove its efficacy in clinical studies, the results of our study concluded that A. blazei extract offers a promising and new therapeutic lead for treatment of PD.

Agaricus blazei extract attenuates rotenone-induced apoptosis through its mitochondrial protective and antioxidant properties in SH-SY5Y neuroblastoma cells.

The present study was aimed to find out the effect of Agaricus blazei mushroom extract against rotenone-induced cellular model. SH-SY5Y neuroblastoma cells are divided into four experimental groups (control, rotenone (100 nM), A. blazei (5 µg/ml) + rotenone (100 nM), and A. blazei alone treated) based on MTT assay, cells were allowed to measure the ROS, TBARS levels, and antioxidants activities. Finally, mitochondrial transmembrane potential (MMP) and expressions of apoptotic proteins were also analyzed. Pre-treatment with A. blazei significantly enhanced cell viability, attenuated rotenone-induced ROS, MMP, and apoptosis. Our results indicated that anti-apoptotic properties of this natural compound due to its antioxidant and mitochondrial protective function protect rotenone-induced cytotoxicity. Therefore, it may be concluded that A. blazei can be further developed as a promising drug for the treatment of Parkinson's disease (PD).

Neuroprotective effect of Demethoxycurcumin, a natural derivative of Curcumin on rotenone induced neurotoxicity in SH-SY 5Y Neuroblastoma cells.

BACKGROUND: Mitochondrial dysfunction and oxidative stress are the main toxic events leading to dopaminergic neuronal death in Parkinson's disease (PD) and identified as vital objective for therapeutic intercession. This study investigated the neuro-protective effects of the demethoxycurcumin (DMC), a derivative of curcumin against rotenone induced neurotoxicity. METHODS: SH-SY5Y neuroblastoma cells are divided into four experimental groups: untreated cells, cells incubated with rotenone (100 nM), cells treated with DMC (50 nM) + rotenone (100 nM) and DMC alone treated. 24 h after treatment with rotenone and 28 h after treatment with DMC, cell viability was assessed using the MTT assay, and levels of ROS and MMP, plus expression of apoptotic protein were analysed. RESULTS: Rotenone induced cell death in SH-SY5Y cells was significantly reduced by DMC pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of DMC. Rotenone treatment significantly increases the levels of ROS, loss of MMP, release of Cyt-c and expression of pro-apoptotic markers and decreases the expression of anti-apoptotic markers. CONCLUSIONS: Even though the results of the present study indicated that the DMC may serve as a potent therapeutic agent particularly for the treatment of neurodegenerative diseases like PD, further pre-clinical and clinical studies are required.

Aspartoacylase deficiency in the white matter of human immunodeficiency virus encephalitis: novel mechanism in axonal damage.

Aspartoacylase/aminoacylase II (ASPA/ACY II) is mainly synthesized in oligodendrocytes to contribute in myelin synthesis. Although axonal damage is seen in the brain with human immunodeficiency virus encephalitis (HIVE), ASPA contribution in the pathology is not known. Immunostaining study showed that ASPA protein is reduced in the white matter of patients with HIVE compared to the control. Western blot study further confirmed ASPA deficiency in the HIVE brain compared to the control. This paper suggests that HIVE condition affects ASPA to contribute in myelin loss/axonal damage seen in the disease.

Parkinson's disease: oxidative stress and therapeutic approaches.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by reduced levels of catecholamines and oxidative stress. Symptoms seen in the disease include tremor, rigidity, bradykinesia and postural disability. Oxidative stress plays a key role in neurodegeneration and motor abnormalities seen in PD. Altered levels of the protein caused by these changes lead to defective ubiquitin-proteasome pathway. Neurodegeneration seen in PD and Canavan disease has a common mechanism. Recent studies suggest that herbal medicines can improve molecular changes and motor functions seen in PD.

Resveratrol attenuates oxidative stress and improves behaviour in 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenged mice.

BACKGROUND: Parkinson's disease (PD) is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to mitochondrial dysfunction, oxidative stress, excitotoxicity, apoptosis, inflammation and proteasome failure. PURPOSE: The present study deals with the neuroprotective effect of resveratrol, a wine polyphenol (50 mg/kg body weight) against MPTP (30mg/kg body weight as i.p. administration) induced mice model of idiopathic Parkinson's disease. METHODS: A combination of behaviour tasks and biochemical parameters were tested using standard molecular tools. RESULTS: Pretreatment of resveratrol significantly reversed toxic effects of MPTP by increasing the levels of dopamine, its metabolites, GSH and activities of GPx and reducing levels of TBARS, catalase and SOD activities along with enhanced behavior performance. CONCLUSION: The multifactorial etiology of these diseases suggests that drugs with multiple targets such as resveratrol could have therapeutic potential for these pathologies.

Withania somnifera root extract improves catecholamines and physiological abnormalities seen in a Parkinson's disease model mouse.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera root extract (Ws)/Ashwagandha/Indian ginseng is a traditional herbal medicine, used over 4000 years in India, shown to have effect on neural growth and locomotor function. Although catecholamines and oxidative stress resulting in neurodegeneration and locomotor disorder are the main events in Parkinson's disease (PD), efficacy of the drug on these molecules and physiological abnormality are not clear. AIM OF THE STUDY: The objective of the study was to examine effect of Ws on catecholamines and physiological abnormalities seen in PD using PD model mouse. MATERIALS AND METHODS: Mouse were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days to show biochemical and physiological abnormalities similar to patients with PD. PD mice were treated with Ws 100mg/kg body weight for 7 or 28 days. Catecholamines: dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA); antioxidants: glutathione (GSH) and glutathione peroxidase (GPx); and lipid peroxidation marker (TBARS) were analyzed in the Ws treated and untreated PD mouse striatum. RESULTS: Mouse treated with MPTP showed reduced levels of DA, DOPAC, HVA, GSH and GPx and induced thiobarbituric acid reactive substance (TBARS) level compared to the control. Physiological abnormalities were seen in the mouse as determined by hang test and rotarod test. Oral treatment of PD mouse Ws root extract (100mg/kg body weight) for 7 days or 28 days increased DA, DOPAC and HVA levels and normalized TBARS levels in the corpus striatum of the PD mouse. The 7 days Ws treated mice showed improved motor function as determined by hang test and rotarod test. Treatment with Ws for 28 days increased GSH and GPx levels in the striatum compared to the Ws untreated PD mouse striatum. CONCLUSION: These data suggest that Ws is a potential drug in treating catecholamines, oxidative damage and physiological abnormalities seen in the PD mouse.

Ashwagandha leaf extract: a potential agent in treating oxidative damage and physiological abnormalities seen in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that leads to impairment of balance and coordination. Therapy for the disease is still under investigation. Withania somnifera (A-Extract), a herbal medicine, has been known for a spectrum of health-promoting effects including activation of immune, muscle and neuronal systems. Therefore effect of A-Extract in the mouse model of PD was examined. The midbrain and corpus striatum of PD mouse showed increased levels of superoxide dismutase, catalase and malondialdehyde; and reduced levels of glutathione and glutathione peroxidase compared to the control. Treatment with A-Extract 100mg/kg for 7 days significantly improved all these enzyme levels compared to A-Extract untreated PD mouse brain. In the PD mouse grooming, stride length, movement, rearing were found to be decreased compared to the control. In addition, narrow beam walk and foot slippery errors were increased. Treatment with A-Extract improved all these physiological abnormalities. These data suggests that A-Extract is a potential drug in treating oxidative damage and physiological abnormalities seen in the PD mouse, if documented also in patients with PD.

Antioxidant effect of 2-hydroxy-4-methoxy benzoic acid on ethanol-induced hepatotoxicity in rats.

Alcoholic liver disease (ALD) is one of the most common diseases in society. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of ALD. 2-Hydroxy-4-methoxy benzoic acid (HMBA), the active principle of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant in India, is expected to significantly inhibit the development of liver injury in ethanol administration. It is expected to reduce the severity of liver damage in terms of body weight, hepatic marker enzymes, oxidative stress, antioxidant status and histological changes in ethanol-induced hepatotoxic rats. Hepatotoxicity was induced by administering 20% ethanol (5 g kg(-1) daily) for 60 days to male Wistar rats, which resulted in significantly decreased body weight and an increase in liver-body weight ratio. The liver marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase and lactate dehydrogenase were elevated. In addition, the levels of plasma, erythrocyte and hepatic thiobarbituric acid reactive substances, hydroperoxides and conjugated dienes were also elevated in ethanol-fed rats as compared with those of the experimental control rats. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and alpha-tocopherol was also observed on alcohol administration as compared with experimental control rats. HMBA was co-administered at a dose of 200 mug kg(-1) daily for the last 30 days of the experiment to rats with alcohol-induced liver injury, which significantly increased body weight, significantly decreased the liver-body weight ratio, transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and lactate dehydrogenase, significantly decreased the levels of lipid peroxidative markers, significantly elevated the activity of enzymic and non-enzymic antioxidants in plasma, erythrocytes and liver and also increased levels of plasma and liver vitamin C and alpha-tocopherol at the end of the experimental period as compared with untreated ethanol-administered rats. The histological changes were also in correlation with the biochemical findings. The results suggest that HMBA administration may afford protection against ethanol-induced liver injury in rats.