minocycline and Parkinson-Disease--Secondary

Parkinson's disease (PD) is a motor scarcity disorder characterized by the striatal dopamine deficiency owing to the selective degeneration of the nigrostriatal dopaminergic neurons. While oxidative stress is implicated in PD, prolonged exposure to moderate dose of cypermethrin induces Parkinsonism. The study aimed to investigate the status of oxidative stress indicators and antioxidant defence system of the polymorphonuclear leukocytes (PMNs), platelets and plasma to delineate the effect of Parkinsonian dose of cypermethrin in the peripheral blood of rats and its subsequent relevance to Parkinsonism. Nitrite content, lipid peroxidation (LPO) and activity of superoxide dismutase (SOD), catalase, glutathione reductase (GR) and glutathione-S-transferase (GST) were measured in the PMNs, platelets and plasma of control and cypermethrin-treated rats in the presence or absence of a microglial activation inhibitor, minocycline or a dopamine precursor containing the peripheral 3,4-dihydroxyphenylalanine decarboxylase inhibitor, named syndopa, employing the standard procedures. The striatal dopamine was measured to assess the degree of neurodegeneration/neuroprotection. Cypermethrin increased nitrite and LPO in the plasma, platelets and PMNs while it reduced the striatal dopamine content. Catalase and GST activity were increased in the PMNs and platelets; however, it was reduced in the plasma. Conversely, SOD and GR activities were reduced in the PMNs and platelets but increased in the plasma. Minocycline or syndopa reduced the cypermethrin-mediated changes towards normalcy. The results demonstrate that cypermethrin alters the status of oxidative stress indicators and impairs antioxidant defence system of the peripheral blood, which could be effectively salvaged by minocycline or syndopa. The results could be of value for predicting the nigrostriatal toxicity relevant to Parkinsonism.

Topics: Animals; Catalase; Corpus Striatum; Dopamine; Glutathione Transferase; Insecticides; Male; Minocycline; Nitrites; Oxidative Stress; Parkinson Disease, Secondary; Pyrethrins; Rats, Wistar; Superoxide Dismutase

Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Disease Models, Animal; Dopamine; Homeodomain Proteins; Levodopa; Male; Maneb; Metalloporphyrins; Mice; Microglia; Minocycline; Mitochondria; Paraquat; Parkinson Disease, Secondary; Proteome; Stathmin; Superoxide Dismutase

Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). However, whether regenerative endogenous neurogenesis is taking place in the mammalian SN of parkinsonian and non-parkinsonian brains remains of debate. Here, we tested whether proliferating cells in the SN and their neurogenic potential would be affected by anti-inflammatory treatment under physiological conditions and in the 6-hydroxy-dopamine (6-OHDA) Parkinson's disease mouse model. We report that the majority of newly generated nigral cells are positive for Doublecortin (Dcx), which is an often used marker for neural progenitor cells. Yet, Dcx expression levels in these cells were much lower than in neural progenitor cells of the subventricular zone and the dentate gyrus neural progenitor cells. Furthermore, these newly generated nigral cells are negative for neuronal lineage markers such as TuJ1 and NeuN. Therefore, their neuronal commitment is questionable. Instead, we found evidence for oligodendrogenesis and astrogliosis in the SN. Finally, neither short-term nor long-term inhibition of neuroinflammation by Minocycline- or 6-OHDA-induced lesion affected the numbers of newly generated cells in our disease paradigm. Our findings of adult generated Dcx(+) cells in the SN add important data for understanding the cellular composition and consequently the regenerative capacity of the SN.

Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; Dopaminergic Neurons; Doublecortin Domain Proteins; Doublecortin Protein; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Minocycline; Neural Stem Cells; Neurogenesis; Neuropeptides; Oxidopamine; Parkinson Disease, Secondary; Substantia Nigra