articlesParkinson's disease is a late-onset, progressive motor disease marked by selective degeneration of dopaminergic neurons of the substantia nigra and formation of fibrillar cytoplasmic inclusions, known as Lewy bodies, which contain ubiquitin and α-synuclein 1 . Rare cases of familial PD have been linked to mutations in α-synuclein or parkin [2][3][4] , but the cause of the more commonly encountered sporadic disease is unknown, and the role of genetics in these cases is uncertain 5 . Post mortem studies strongly implicate oxidative damage and mitochondrial impairment in the pathogenesis of PD 6 . Epidemiological studies have suggested that pesticide exposure is associated with an increased risk of developing PD 7-9 .After the pro-toxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was reported to produce in humans an acute parkinsonian syndrome that is virtually indistinguishable from idiopathic PD 10 , its metabolite, 1-methyl-4-pyridinium (MPP + ), was found to be a mitochondrial poison that inhibits mitochondrial respiration at complex I of the electron transport chain 11,12 . The selectivity of MPP + for dopaminergic neurons is due to the fact that it is an excellent substrate for the dopamine transporter, and is thereby accumulated preferentially in cells that transport dopamine 13 . Following recognition of MPTP's toxicity and its mechanism of action, several laboratories reported a selective defect in complex I of the electron transport chain in PD [14][15][16][17][18][19][20][21][22] . This defect seems to be systemic, affecting not only the brain, but also peripheral tissues such as platelets.An accurate in vivo experimental model of PD should reproduce the progressive, selective nigrostriatal dopaminergic degeneration and Lewy body formation seen in PD, test the relevance of the systemic complex I defect, and explain the potential involvement of pesticide exposure in development of parkinsonism. Unfortunately, no current animal model incorporates all of these features. The MPTP model causes selective nigrostriatal degeneration by inhibiting complex I, but, unlike PD, MPTP does not cause a systemic complex I defect. Instead, the inhibition is highly selective for dopaminergic neurons. Moreover, MPTP does not typically produce cytoplasmic inclusions that closely resemble Lewy bodies 23 . Transgenic mice expressing the pathogenic human α-synuclein mutation develop modest dopaminergic pathology (although the specificity of this degeneration is not detailed), and many neurons contain small cytoplasmic inclusions that are granular rather than fibrillar 24 .To develop a more accurate in vivo model of PD, we exposed rats chronically, continuously and systemically to the common pesticide, rotenone. A naturally occurring compound derived from the roots of certain plant species, rotenone is commonly used as an insecticide in vegetable gardens, and is also used to kill or sample fish populations in lakes and reservoirs. It is widely believed to be a safe, natural alternative to synthetic pesticides. Ro...

The cause of Parkinson's disease (PD) is unknown, but reduced activity of complex I of the electron-transport chain has been implicated in the pathogenesis of both mitochondrial permeability transition pore-induced Parkinsonism and idiopathic PD. We developed a novel model of PD in which chronic, systemic infusion of rotenone, a complex-I inhibitor, selectively kills dopaminergic nerve terminals and causes retrograde degeneration of substantia nigra neurons over a period of months. The distribution of dopaminergic pathology replicates that seen in PD, and the slow time course of neurodegeneration mimics PD more accurately than current models. Our model should enhance our understanding of neurodegeneration in PD. Metabolic impairment depletes ATP, depresses Na+/K(+)-ATPase activity, and causes graded neuronal depolarization. This relieves the voltage-dependent Mg2+ block of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, which is highly permeable to Ca2+. Consequently, innocuous levels of glutamate become lethal via secondary excitotoxicity. Mitochondrial impairment also disrupts cellular Ca2+ homoeostasis. Moreover, the facilitation of NMDA-receptor function leads to further mitochondrial dysfunction. To a large part, this occurs because Ca2+ entering neurons through NMDA receptors has 'privileged' access to mitochondria, where it causes free-radical production and mitochondrial depolarization. Thus there may be a feed-forward cycle wherein mitochondrial dysfunction causes NMDA-receptor activation, which leads to further mitochondrial impairment. In this scenario, NMDA-receptor antagonists may be neuroprotective.

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

SUMMARY The effects of intermittent maximal exercise (galloping) before and after a 10 week training programme were studied in 6 horses. Determinations were carried out on venous blood for packed cell volume, total plasma protein, glucose, glycerol, free fatty acids, lactate, 11‐hydroxycorticosteroids, blood gases and pH. There were marked changes associated with galloping and some of these could be modified with training. The major findings included (i) an elevated blood glucose, (ii) a large increase in glycerol, which was greatest at 30 min post‐exercise and was higher following training, (iii) smaller increases in free fatty acids following training, (iv) higher levels of lactate after training, (v) a marked fall in pH which was less after training, (vi) an increase in 11‐hydroxycorticosteroids with possibly a more rapid return to resting levels following training. It was concluded that with maximal exercise in the horse both glycogen and free fatty acids served as important substrates for working muscle, and following training greater utilisation of both these substrates occurred. RÉSUMÉ Les effets de galops effectués avant et après un programme d'entrainement de 10 semaines ont étéétudiés chez six chevaux. Les recherches ont porté sur l'hématocrite, les protéines du plasma, le glucose, le glycerol, les acides gras non saturés, les lactates, les 11 cortico steroides, les gaz du sang et le pH. Des changements importants suivirent les épreuves de galop, et ces changements se trouvèrent modifiés par l'entrainement. On trouva en particulier: 1) une élévation du glucose sanguin, 2) une élévation marquée du glycerol, dont le pic se manifestait 30 minutes après l'effort et se révélait supérieur après l'entrainement, 3) une légère augmentation des acides gras après entrainement, 4) une élévation des lactates après entrainement, 5) une chute notable du pH après galop, moindre après entrainement, 6) un accroissement des 11 cortico steroides avec peut‐être un retour plus rapide aux valeurs de repos après entrainement. On conclue que pour l'effort maximum chez le cheval les muscles utilisént comme substrat en particulier les acides gras non saturés et le glycogène. ZUSAMMENFASSUNG Die Auswirkungen einer intermittierenden, maximalen Anstrengung vor und nach einem 10‐wöchigen Training wurde an sechs Pferden untersucht. Gemessen wurden in venösem Blut: Haematocrit, Gesamtprotein, Glucose, Glycerin, freie Fettsäure Laktat, 11‐Hydroxycorticosteroide, Blutgase und pH. Es zeigten sich nach der Galloparbeit deutliche Veränderungen, unter denen ein Teil mit dem Training modifiziert werden konnte. Die wichtigsten Resultate bestanden in a) erhöhter Glucosekonzentration, b) stark erhöhter Glycerinkonzentration mit einem Gipfel 30 Minuten nach Anstrengung; diese Erhöhung war nach der Trainingsperiode ausgeprägter, c) geringeren Erhöhungen der Spiegel freier Fettsäuren nach dem Training, d) höherem Laktatspiegel nach dem Training, e) deutlicher Abnahme des pH, weniger ausgeprägt nach dem Training, f) Erhöhung der 11‐Hydroxycorticoste...

The pathogenesis of H. contortus infection in lambs under 6 months of age challenged orally with 10,000 third stage infective larvae is described. The development of the parasite and its relationship to haematological and pathological changes are discussed, with particular reference to specific cellular mobilizations, and detailed descriptions are given of the haematology and parasitology, gross pathology and histopathology at 4, 7, 12, 18, 22 and 35 days after infection. Dramatic changes had developed by day 12.