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Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 91 records · Page 5Linked to original sources
PubMed1999

Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures.

Altered glial function in the substantia nigra in Parkinson's disease may lead to the release of toxic substances that cause dopaminergic cell death or increase neuronal vulnerability to neurotoxins. To investigate this concept, we examined the effects of subjecting astrocytes to lipopolysaccharide (LPS)-induced activation alone or combined with L-buthionine-[S,R]-sulfoximine-induced glutathione depletion or inhibition of complex I activity by 1-methyl-4-phenylpyridinium (MPP+) on the viability of primary ventral mesencephalic neurones or susceptibility to MPP+ and 6-hydroxydopamine (6-OHDA) in co-cultures. LPS-activated astrocytes caused neuronal death in a time-dependent manner, but glutathione-depleted or complex I-inhibited astrocytes had no effect on neuronal viability. The neurotoxicity of LPS-activated astrocytes was inhibited by the inducible nitric oxide synthase inhibitor aminoguanidine, by the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and by reduced glutathione (GSH). MPP+-induced neuronal death was greater in ventral mesencephalic cultures previously cultured with LPS-activated, glutathione-depleted, or complex I-inhibited astrocytes compared with co-cultures containing normal astrocytes. The increased neuronal susceptibility to MPP+ caused by LPS-activated or complex I-inhibited astrocytes and glutathione-depleted astrocytes was inhibited by the NMDA/glutamate antagonist MK-801 and by GSH, respectively. Neuronal death caused by 6-OHDA was increased in ventral mesencephalic cultures previously cultured with LPS-activated and glutathione-depleted, but not complex I-inhibited astrocytes, compared with co-cultures containing normal astrocytes. Treatment of co-cultures with GSH prevented the increased neuronal susceptibility to 6-OHDA. These findings suggest that glial dysfunction may cause neuronal death or render neurones susceptible to toxic insults via a mechanism involving the release of free radicals and glutamate. Such a mechanism may play a role in the development or progression of nigrostriatal degeneration in Parkinson's disease.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease.

The cause of neurodegeneration in Parkinson's disease (PD) remains unknown. However, isoquinoline derivatives structurally related to the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinim (MPP+), have emerged as candidate endogenous neurotoxins causing nigral cell death in Parkinson's disease. Isoquinoline derivatives are widely distributed in the environment, being present in many plants and foodstuffs, and readily cross the blood-brain barrier. These compounds occur naturally in human brain where they are synthesized by non-enzymatic condensation of biogenic amines (e.g. catecholamines and phenylethylamine) with aldehydes, and are metabolized by cytochrome P450s and N-methyltransferases. In addition, isoquinoline derivatives are oxidized by monoamine oxidases to produce isoquinolinium cations with the concomitant generation of reactive oxygen species. Neutral and quaternary isoquinoline derivatives accumulate in dopaminergic nerve terminals via the dopamine re-uptake system, for which they have moderate to poor affinity as substrates. Several isoquinoline derivatives are selective and more potent inhibitors of NADH ubiquinone reductase (complex I) and alpha-ketoglutarate dehydrogenase activity in mitochondrial fragments than MPP+, and lipophilicity appears to be important for complex I inhibition by isoquinoline derivatives. However, compared with MPP+, isoquinoline derivatives are selective but less potent inhibitors of NADH-linked respiration in intact mitochondria, and this appears to be a consequence of their rate-limiting ability to cross mitochondrial membranes. Although both active and passive processes are involved in the accumulation of isoquinoline derivatives in mitochondria, inhibition of respiration is determined by steric rather than electrostatic properties. Compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPP+, isoquinoline derivatives show selective but relatively weak toxicity to dopamine-containing cells in culture and following systemic or intracerebral administration to experimental animals, which appears to be a consequence of poor sequestration of isoquinoline derivatives by mitochondria and by dopamine-containing neurones. In conclusion, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-like cytotoxic characteristics of isoquinoline derivatives and the endogenous/environmental presence of these compounds make it conceivable that high concentrations of and/or prolonged exposure to isoquinoline derivatives might cause neurodegeneration and Parkinson's disease in humans.

Animals↗
PubMed1998

Adenosine A2A receptors modify motor function in MPTP-treated common marmosets.

Both adenosine A1 and A2 receptor populations are located in the striatum and can modify locomotor activity, and they may form a therapeutic target for Parkinson's disease (PD). Administration of the selective adenosine A2A antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-pu rine-2,6-dione (KW-6002) to MPTP-treated common marmosets increased locomotor activity. In contrast, administration of the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxantine (DPCPX) had no effect on locomotion. Administration of the adenosine A2A receptor agonist 2-[p-[2-(2-aminoethylamino) carbonylethyl] phenethyl amino]-5'-N-ethylcarboxamidoadenosine (APEC) dose dependently suppressed basal locomotor activity. A minimally effective dose of APEC (0.62 mg/kg, i.p) completely reversed the increase in locomotor activity produced by administration of KW-6002. The adenosine A2A receptor appears to be an important target for the treatment of basal ganglia disorders, particularly PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Mitochondrial function, GSH and iron in neurodegeneration and Lewy body diseases.

The cause of neuronal loss in patients with idiopathic Parkinson's disease is unknown. Oxidative stress and complex I deficiency have both been identified in the substantia nigra in Parkinson's disease but their place in the sequence of events resulting in dopaminergic cell death is uncertain. We have analysed respiratory chain activity, iron and reduced glutathione concentrations in Parkinson's disease substantia innominata and in the cingulate cortex of patients with Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies to investigate their association with neuronal death and Lewy body formation. No abnormalities of mitochondrial function, iron or reduced glutathione levels were identified in Parkinson's disease substantia innominata or cingulate cortex. Mitochondrial function also appeared to be unchanged in cingulate cortex from patients with Alzheimer's disease and from patients with dementia with Lewy bodies, however, iron concentrations were mildly increased in both, and reduced glutathione decreased only in Alzheimer's disease. These results confirm the anatomic specificity of the complex I deficiency and decreased levels of reduced glutathione within the Parkinson's disease brain and suggest that these parameters are not associated with cholinergic cell loss in Parkinson's disease nor with Lewy body formation in this or other diseases. We propose that our data support a 'two-hit' hypothesis for the cause of neuronal death in Parkinson's disease.

Aged↗
PubMed1998

Sulphite enhances peroxynitrite-dependent alpha1-antiproteinase inactivation. A mechanism of lung injury by sulphur dioxide?

Sulphite is toxic to the lung and can cause allergic reactions, the most common of which is bronchoconstriction in asthmatics. We show that sulphite can considerably potentiate the inactivation of alpha1-antiproteinase caused by peroxynitrite. Addition of peroxynitrite to sulphite generated inactivating species that persisted at pH 7.4 and 37 degrees C for at least 30 min. We propose that formation of protein-modifying sulphite radicals from SO3(2-) exposed to ONOO- is a mechanism by which SO2 could cause lung injury, both by enhancing proteolysis and by creating new antigens that could provoke an immune response.

Asthma↗
PubMed1998

L-arginine produces NO-independent increases in dopamine efflux in rat striatum.

The effect of L-arginine (L-ARG; 10-100 mM) on dopamine efflux from rat striatum was investigated using in vivo microdialysis. L-ARG (50 mM-100 mM), but not D-arginine (100 mM) nor L-citrulline (100 mM), produced a biphasic effect on dopamine efflux with an initial small reduction, followed by a large sustained increase. The effect of L-ARG was not prevented by nitric oxide synthase inhibition with NG-nitro-L-arginine methyl ester or 7-nitroindazole monosodium salt. Efflux of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was reduced by L-ARG (10-100 mM), D-arginine (100 mM) and L-citrulline (100 mM). These data suggest that changes in dopamine, DOPAC and HVA efflux produced by high concentrations of L-ARG occur independently of NO, and that the use of high L-ARG concentrations are inappropriate when investigating the role of NO in striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys.

Treatment of Parkinson's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Understanding cell death in Parkinson's disease.

Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, alpha-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.

Cell Death↗
PubMed1998

Dopamine agonists and neuroprotection in Parkinson's disease.

There is increasing interest in the potential of dopamine agonists to provide a neuroprotective effect and to alter the natural course of levodopa-treated Parkinson's disease (PD). Theoretically, such a protective effect might derive from (a) a levodopa sparing effect, (b) stimulation dopamine autoreceptors resulting in decreased dopamine synthesis, release, and turnover, (c) direct anti-oxidant effects, and (d) restoration of dopaminergic tone to the dopamine-denervated brain so as to restore inhibition to the subthalamic nucleus and thereby diminish STN-mediated excitotoxicity. Preclinical studies have demonstrated that dopamine agonists reduce dopamine formation in comparison to levodopa, protect cultured dopaminergic neurons from a variety of toxins including levodopa, and protect dopaminergic neurons from toxins and age-related degeneration in some rodent models of parkinsonism. Based on these findings, several clinical trials have been initiated in patients with early PD to test the effect of dopamine agonists on clinical and neuroimaging markers of disease progression.

Animals↗
PubMed1998

P450 enzymes and Parkinson's disease: the story so far.

Environmental or endogenous toxins may cause nigral cell death in Parkinson's disease (PD) as a result of genetic susceptibility conferred by altered expression of P450 enzymes. Attention over the last 10 years has focused on CYP2D6 polymorphisms and susceptibility to PD. This review summarizes reports arising from both phenotypic and genotypic studies involving CYP2D6 and PD. Phenotypic studies have failed to support a link between CYP2D6 and PD. The more powerful genetic studies initially indicated a link between CYP2D6B mutations and PD, but critical analysis of the literature and recent studies emerging from independent laboratories fail to confirm this. Mutations in CYP2D6B are also not implicated in familial PD. As yet, there is no conclusive evidence to suggest that CYP2D6 polymorphisms confer susceptibility to PD. Whether polymorphisms in other P450s (for example, CYP1A1 and CYP2E1) are implicated in PD remains to be established.

Animals↗
PubMed1998

De novo administration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in the MPTP-treated marmoset.

In contrast to levodopa (L-dopa), de novo administration of the D2-like receptor agonist bromocriptine to patients with Parkinson's disease (PD) or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates is not associated with the onset of significant dyskinesia. We now compare the ability of the novel D2-like selective dopamine agonist ropinirole with that of bromocriptine and L-dopa to induce dyskinesia in MPTP-treated common marmosets. MPTP-treated common marmosets were treated with placebo, L-dopa plus carbidopa, ropinirole, or bromocriptine daily for 30 days (n = 4 per group) in doses that were titrated to similarly increase locomotion and improve motor disability. L-dopa rapidly induced dyskinesia of moderate to severe intensity, whereas ropinirole and bromocriptine produced mild dyskinesia over the course of the study that was significantly less severe than in the L-dopa-treated group (p < 0.05). However, in a separate group of marmosets previously primed with L-dopa to exhibit dyskinesia, ropinirole administration elicited severe dyskinesias comparable with that of L-dopa in a dose-dependent fashion. Ropinirole, in common with bromocriptine, has a lesser tendency than L-dopa to produce dyskinesia while similarly improving motor performance in drug-naive MPTP-treated marmosets. However, in common with other dopamine agonists, ropinirole will elicit comparable dyskinesia once L-dopa priming has occurred. These results predict a similar response to ropinirole and other long-acting dopamine agonists in L-dopa-naive patients with PD and emphasize the importance of avoiding initial dyskinesia induction through early use of dopamine agonist drugs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Co-localization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase.

Susceptibility to develop Parkinson's disease has been linked to abnormalities of P450 enzyme function. Multiple P450 enzymes are expressed in brain but the relationship of these to Parkinson's disease is unknown. We have investigated the expression of P450 enzymes in the rat substantia nigra and their co-localization in tyrosine hydroxylase-positive neurons and astrocytes. Immunohistochemistry was performed using anti-peptide antisera against the following P450 enzymes: CYP1A1, CYP1A2, CYP2B1/2, CYP2C12, CYP2C13/2C6, CYP2D1, CYP2D4, CYP2E1, CYP3A1, CYP3A2 and NADPH-P450 oxidoreductase. Immunoreactivity in nigral cells was found only for CYP2E1 and CYP2C13/2C6. CYP2E1 immunoreactivity was localized to many midbrain nuclei including the substantia nigra pars compacta but not the substantia nigra pars reticulata while immunoreactivity to CYP2C13/2C6 was found in the substantia nigra pars compacta, substantia nigra pars reticulata and many other midbrain nuclei. Sections of rat midbrain double labelled for either CYP2E1 or CYP2C13/2C6 and tyrosine hydroxylase or glial fibrillary acidic protein were examined for co-localization by confocal laser scanning microscopy. CYP2E1 and CYP2C13/2C6 immunoreactivity was found in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta but not in glial cells. CYP2C13/2C6, but not CYP2E1, was also found in non-glial, non-tyrosine hydroxylase-expressing cells in the substantia nigra pars reticulata. Isoniazid induction increased CYP2E1 fluorescence signal intensity from nigral dopaminergic neurons. At least two P450 enzymes are found in nigral dopamine containing cells and one, namely CYP2E1, is selectively localized to this cell population. CYP2E1 is a potent generator of free radicals which may contribute to nigral pathology in Parkinson's disease. The expression of CYP2E1 in dopaminergic neurons in substantia nigra raises the possibility of a causal association with Parkinson's disease.

Animals↗
PubMed1998

High efficiency gene transfer to the central nervous system of rodents and primates using herpes virus vectors lacking functional ICP27 and ICP34.5.

The safe and efficient use of herpes simplex virus (HSV)-based vectors to deliver genes of potentially therapeutic benefit to the central nervous system will require their effective disablement by the inactivation of viral genes required for lytic growth. Here we report that viruses lacking functional genes for ICP27 (which is required for growth in all cell types) and ICP34.5 (which is required for growth in nondividing cell types) can deliver a marker gene to both the rodent and primate CNS with high efficiency whilst producing relatively minimal damage and having no effect on sodium currents in dorsal root ganglion neurons. Such viruses paradoxically deliver genes at much higher efficiency than the less disabled single mutant lacking ICP34.5 alone and also, as expected, produce less damage in vivo. Moreover, unlike the single mutant lacking ICP27 the double mutant viruses cannot revert to wild-type by acquistion of complimenting gene sequences during growth of virus stocks in vitro on dividing cells expressing ICP27 since artificial expression of ICP34.5 in these cells is not required. Such ICP27-; ICP34.5- viruses thus offer a platform for the development of vectors which are sufficiently safe for ultimate use in human gene therapy.

Animals↗
PubMed1998

Artefacts in HPLC detection of 3-nitrotyrosine in human brain tissue.

An HPLC method was used for quantification of 3-nitrotyrosine (3-NT) in human postmortem brain tissue. A peak with similar retention time to 3-NT was detected in brain tissue from patients with Parkinson's disease, Huntington's chorea, multiple system atrophy, and Alzheimer's disease but not in control tissue. The peak was lost on reduction with dithionite, a criterion often used to identify 3-NT. Tissue from the same neurodegenerative diseases was analysed by HPLC using a photodiode array detector in series with an amperometric electrochemical detector, but the peak was found not to be 3-NT. The absorbance spectrum, fragmentation pattern on mass spectroscopy, and electrochemical profile of this peak do not match authentic 3-NT. A search of the mass spectroscopy databases failed to reveal its identity. The presence of this closely eluting, dithionite-reducible peak could confound analysis of human tissues for 3-NT. In vitro experiments showed that high concentrations of peroxynitrite were needed to achieve detectable levels of 3-NT in human brain tissue.

Artifacts↗
PubMed1998

Oxidative damage to proteins, lipids, and DNA in cortical brain regions from patients with dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) forms the second most common pathological subgroup of dementia after Alzheimer's disease. The present study compares the levels of oxidative damage to proteins, lipids, and DNA bases in cortical brain areas from patients with DLB with levels in matched control tissues. Overall, there was a trend for protein carbonyl levels to be increased in all areas, but a significant difference was found only in the parietal and temporal lobes. No differences were observed in the levels of lipid peroxidation. Measurement of products of damage to DNA bases showed increased levels of thymine glycol, 8-hydroxyguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 5-hydroxycytosine, 5-hydroxyuracil, 5-hydroxymethyluracil, and xanthine. Xanthine levels were increased in the DLB group in the parietal, occipital, and temporal lobes, indicating that peroxynitrite or other deaminating species may be involved. The finding of increased protein carbonyls and increased DNA base products in cortical regions from DLB patients indicates that oxidative stress may play a role in DLB.

Adenine↗