It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson’s disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how this relates to protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson’s disease.

No abstract

The A/VN/1203/04 H5N1 influenza virus is capable of infecting the CNS of mice and inducing a number of neurodegenerative pathologies. Here, we examined the effects of H5N1 on several pathological aspects affected in parkinsonism, including loss of the phenotype of dopaminergic (DAergic) neurons located in the substantia nigra pars compacta (SNpc), expression of mono- and indolamines in brain, alterations in SNpc microglia number and morphology, and expression of cytokines, chemokines and growth factors. We find that H5N1 induces a transient loss of the DAergic phenotype in SNpc and now report that this loss recovers by 90 days post infection (dpi). A similar pattern of loss and recovery was seen in monoamine levels of the basal ganglia. The inflammatory response in lung and different regions of the brain known to be targets of the H5N1 virus (brainstem, substantia nigra, striatum, and cortex) were examined at 3, 10, 21, 60 and 90 dpi. We found a significant increase in the number of activated microglia in each of these brain regions that lasted at least 90 days. We also quantified expression of IL-1α, IL-1β, IL-2, IL-6, IL-9, IL-10, IL-12(p70), IL-13, TNF-α, IFN-γ, GM-CSF, G-CSF, M-CSF, eotaxin, IP-10, KC, MCP-1, MIP-1α, MIP-1β and VEGF and find that the pattern and levels of expression are dependent on both brain region and time after infection. We conclude that H5N1 infection in mice induces a long-lasting inflammatory response in brain and may play a contributing factor in the development of pathologies in neurodegenerative disorders.

The cause of 95% of Parkinson's disease (PD) cases is unknown. It is hypothesized that PD arises from an interaction of free-radicalgenerating agents with an underlying genetic susceptibility to these compounds. Here we use the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism to examine the role of a dual function protein, GST, in dopaminergic neuron death. GST is the only GST family member expressed in substantia nigra neurons. GST reduction by pharmacological blockade, RNA inhibition, and gene targeting increases sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, suggesting that differential expression of GST contributes to the sensitivity to xenobiotics in the substantia nigra and may influence the pathogenesis of reactive oxygen species-induced neurological disorders including PD.glutathione ͉ oxidative stress ͉ Parkinson's disease ͉ substantia nigra ͉ detoxification I nhibition of free radicals and the damage they produce is critical for cell survival, particularly in neurons. Glutathione S-transferases (GSTs) are a class of inducible, multifunctional, detoxifying enzymes that catalyze the reduction of hydrophobic electrophiles, like those generated by pesticides and chemotherapeutic compounds (1, 2). In mammals, six classes of cytosolic GSTs have been identified, although only three have been described in the CNS (␣, , and ) (3, 4). Of these three GST isoenzymes, GST has also been shown to inhibit JNK-activated signaling, blocking the phosphorylation of cJUN and apoptosis of the cell (5). Epidemiology and experimental models indicate that several neurological disorders, including idiopathic Parkinson's disease (PD), arise from the combination of a genetic susceptibility and environmental exposure to compounds that generate oxidative stress (6). Although several familial parkinsonian syndromes have been identified (including those that induce cell death by the generation of free radicals), the cause of idiopathic PD remains elusive. Several models of parkinsonism have been developed, including the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Systemic administration of MPTP causes a loss of substantia nigra (SN) dopaminergic neurons by mitochondrial inhibition, protein nitrosylation, and release of intracellular dopamine. Each of these processes results in the secondary elevation of reactive oxygen species in humans, nonhuman primates, and mice (7).Brains of PD patients show numerous indicators of oxidative stress, including decreased levels of glutathione (GSH), increased lipid peroxidation, presence of dopamine quinones, DNA damage, and increases in JNK-mediated activation of c-Jun (8, 9). Neurons in the SN pars compacta (SNpc) are thought to be particularly sensitive to oxidative stress because they contain elevated levels of Fe 3ϩ , ␣-synuclein, and dopamine (10). In the murine MPTP model of parkinsonism, MAO-B in glial cells converts MPTP to 1-methyl-4-phenylpyridinium (MPP ϩ ), which enters dopaminergic neurons through dopamine transporters and blocks complex ...

1. 1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), a racemic mixture of 1-aminocyclopentane-1S,3R-dicarboxylic acid and 1-aminocyclopentane-1R,3S-dicarboxylic acid, a selective agonist of the metabotropic glutamate receptor, was applied to mouse Purkinje neurons (PNs) in culture. Measurements of free intracellular Ca2+ were made using fura-2 microfluorimetric imaging and of membrane current using perforated-patch voltage-clamp recording in separate experiments. 2. Brief pulses of t-ACPD (< or = 100 microM, 1-5 s) consistently produced a large (200-600 nM) increase in dendritic Ca2+ that was sometimes followed by a somatic increase. The dendrites typically returned to basal Ca2+ levels within 10-30 s. 3. Ca2+ increases produced by t-ACPD were measured in Ca(2+)-free external saline [0.5 mM ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)], suggesting that they result from intracellular mobilization rather than influx. In addition, Ca2+ increases were not attenuated by a mixture of DL-AP5 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) [antagonists of N-methyl-D-aspartate (NMDA) and AMPA/kainate receptors, respectively], but were almost entirely eliminated by L-AP3 (100 microM), a putative metabotropic receptor antagonist or by preincubation of the cultures in pertussis toxin. 4. Brief pulses of t-ACPD (10 microM) produced a small inward current that was associated with an increase in membrane conductance. This current was reversibly blocked by L-AP3 but not by treatments that attenuate some voltage-gated K+ currents. Thus this current is unlikely to underlie the depolarization that is produced by metabotropic agonists in hippocampal pyramidal cells by K(+)-channel closure. 5. The t-ACPD induced inward current was attenuated by substitution of external Na+ with Li+ or choline, or by application of the membrane-permeable Ca2+ chelator, bis-(2-aminophenoxy)-N,N,N',N'- tetraacetic acid (BAPTA)/AM. One mechanism that could mediate this current is electrogenic Nao/Cai exchange, triggered by Ca2+ mobilization.