CC BY
61STH MULTIDISCIPLINARY INTERNATIONAL
Conference of Biological Psychiatry
«Stress and Behavior»
Proceedings of the 9th International Multidisciplinary Conference «Stress and behavior» Saint-Petersburg, Russia, 16-19 May 2005 Editor: Allan V. Kalueff, PhD
CONFERENCE ABSTRACTS 1. PSYCHOPHARMACOLOGY
CHRONIC ADMINISTRATION OF ROTENONE INDUCES PARKINSONIC SYMPTOMS AND INCREASES LEVELS OF NITRIC OXIDE IN RAT BRAIN
V. Bashkatova, M. Alam, V. Mikoyan, W.J. Schmidt
Institute of Pharmacology RAMS, Institute of Chemical Physics RAS, Moscow, Russia; University of Tuebingen,
Tuebingen, Germany
Parkinson’s disease (PD) is one of the most widespread neurodegenerative diseases. Pathologically, the hallmark of idiopathic PD is the loss of dopaminergic neurons in the substantia nigra (SN), leading to major clinical abnormalities that characterise this disease. The cause of neuronal loss in the brain is still not known. A reduction of complex I activity has been demonstrated in mitochondria of PD patients and complex I inhibitors such as environmental toxins are involved in some cases of toxic, but not in the majority of sporadic PD. It is well known that the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPP) after its conversion to one of the most prominent mitochondrial complex I inhibitors 1-methyl-4-phenylpyridinium (MPP+), produces PD symptoms. However, till now, there is no adequate experimental model of PD. Recently, it was shown that chronic subcutaneous exposure to low doses of rotenone (an inhibitor of mitochondrial NADH dehydrogenase, a naturally occurring toxin and a commonly used pesticide) caused highly selective nigrostriatal dopaminergic lesions. However, while the behavioral effects of rotenone administration are well characterised, the mechanisms underlying rotenone action are unclear. It is hypothesised that PD is accompanied by a number of neurochemical, cellular and molecular disturbances; these include enhanced generation of free radicals. There are a growing number of recent studies concerning the role of nitric oxide (NO), a molecule, which is regarded as universal neuronal messenger in the pathophysiology of neurodegenerative diseases. The aim of this work is to study mechanisms underlying oxidative damage of the various brain areas of rats produced by rotenone and to investigate a possible role of NO and lipid peroxydation (LPO) processes during chronic rotenone administration.
Methods: Experiments were carried out on male Sprague-Dawley rats. Rotenone at 1.5 mg/kg i. p. was administered to rats daily for 10, 20, 30 and 60 days and NO and TBARS were measured in the frontal and prefrontal cortices, striatum and nucleus accumbences (NAc). Oil was injected as vehicle to the control rats (1 ml/kg). NO generation was directly measured using Electron Paramagnetic Resonance spectroscopy. Specific indexes of LPO (i.e., thiobarbituric acid reactive substances, TBARS) were measured spectrophotometrically.
Results and discussion: NO level in all studied brain structures of rats after first the rotenone injection was not different from that of the control group. In striatum and frontal cortex the level of NO was increased on day 30 and day 6. It has been shown that besides its role as a mediator of several physiological functions, NO appears to be a neurotoxin under conditions of excessive production, which suggests a role for NO in neurodegenerative diseases. NO, generated by the inducible form of nitric oxide synthase (iNOS) in glial cells or the neuronal form (nNOS), can play a key role in the cascade of events leading to the degeneration of neurons. NO-induced catecholamine oxidation could also explain neurotoxcicity in PD by the inherent production of reactive oxygen and nitrogen species. Although NO may act independently, may also act co-operatively with other reactive oxygen species (ROS) to induce neuronal damage. In our study on day 1 and 20 there were slight increases of TBARS in the striatum and frontal cortex but on day 30 and 60 the amount of TBARS was twice higher compared to control in these regions. It was recently demonstrated that a moderate level of complex I inhibition characteristic for PD leads to significant ROS formation. Taken together, these data can be interpreted that dopaminergic neurons may be intrinsically susceptible to oxidative damage as
ISSN l606—8l8l
compared to other neurons. Catalepsy was tested by measuring the descent latency after 30 and 60 days using bar and grid test. Rotenone- treated animals showed a prolonged descent latency as compared to control animals. An increase of descent latency from day 30 to 60 was not observed. Thus, the behavioral data point to decreased dopamine activity.
Conclusion: The findings indicate that chronic administration of rotenone at low dose 1.5 mg/kg significantly enhances the NO generation in all studied brain areas, especially in the NAc and straitum. Moreover, the results provide the first direct evidence that rotenone increases NO tissue level. Our findings also show that treatment with rotenone during 30 and 60 days increases LPO intensity, which points to acute toxicity. The results of this study should advance the understanding of the mechanism of action for pesticides in the pathogenesis of PD, in particular, a role of oxidative damage in the neurotoxicity phenomena induced by administration of rotenone. Supported by grants RFBR 03-04-49050 and RFH 03-06-00085a.
ISSN 1606-8181
