1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson9s disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1β and the activation of NADPH–oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Increased expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E ₂ have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E ₂ synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNK/c-Jun-dependent mechanism after MPTP administration. We demonstrate that targeting COX-2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, we provide evidence that COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood–brain barrier, these drugs may be therapies for PD.

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), however, the means by which neurodegeneration occurs remains obscure. There is evidence that mutant Htt interacts with transcription factors leading to reduced histone acetylation. We report that administration of the histone deacetylase inhibitor phenylbutyrate after onset of symptoms in a transgenic mouse model of HD significantly extends survival and attenuates both gross brain and neuronal atrophy. Administration of phenylbutyrate increased brain histone acetylation and decreased histone methylation levels as assessed by both immunocytochemistry and Western blots. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.

Taurine is a sulfur-containing amino acid and known as semi-essential in mammals and is produced chiefly by the liver and kidney. It presents in different organs, including retina, brain, heart and placenta and demonstrates extensive physiological activities within the body. In the several disease models, it attenuates inflammation- and oxidative stress-mediated injuries. Taurine also modulates ER stress, Ca²⁺ homeostasis and neuronal activity at the molecular level as part of its broader roles. Different cellular processes such as energy metabolism, gene expression, osmosis and quality control of protein are regulated by taurine. In addition, taurine displays potential ameliorating effects against different neurological disorders such as neurodegenerative diseases, stroke, epilepsy and diabetic neuropathy and protects against injuries and toxicities of the nervous system. Several findings demonstrate its therapeutic role against neurodevelopmental disorders, including Angelman syndrome, Fragile X syndrome, sleep-wake disorders, neural tube defects and attention-deficit hyperactivity disorder. Considering current biopharmaceutical limitations, developing novel delivery approaches and new derivatives and precursors of taurine may be an attractive option for treating neurological disorders. Herein, we present an overview on the therapeutic potential of taurine against neurological disorders and highlight clinical studies and its molecular mechanistic roles. This article also addresses the neuropharmacological potential of taurine analogs.

Covering: 2000 to 2013 Oxidative stress is the central component of chronic diseases. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway is vital in the up-regulation of cytoprotective genes and enzymes in response to oxidative stress and treatment with certain dietary phytochemicals. Herein, we classify bioactive compounds derived from natural products that are Nrf2/ARE pathway activators and recapitulate the molecular mechanisms for inducing Nrf2 to provide favorable effects in experimental models of chronic diseases. Moreover, pharmacological inhibition of Nrf2 signalling has emerged as promising strategy against multi-drug resistance thereby improving the treatment efficacy. We have also enlisted natural product-derived inhibitors of Nrf2/ARE pathway.