The Rotenone Model Of Parkinson Disease

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

Get Instant Access

A. Mitochondrial Impairment in the Rotenone Model

To model the systemic defect in complex I reported in PD, researchers have used rotenone exposure. Rotenone is a commonly used pesticide and potent, specific inhibitor of mitochondrial complex I. Although MPP+ is a mitochon-drial toxin, it is not well suited to mimic the systemic mito-chondrial impairment that occurs in PD. MPP+ is a substrate for the dopamine transporter and depends on expression of the dopamine transporter to gain access to cells (Javitch and Snyder 1984). Thus, MPP+ inhibits complex I activity solely in dopaminergic neurons. Rotenone, on the other hand, because of its lipophilic nature, crosses biological membranes easily and independent of transporters. As a result, systemic rotenone exposure inhibits complex I uniformly throughout brain (Betarbet et al. 2000). This model system addresses whether the nigrostriatal dopaminergic pathway is intrinsically sensitive to complex I impairment.

B. Routes of Administration and Animal Strains

Most studies using the rotenone model of PD use chronic treatment regimens. Rotenone gains access to the brain whether given intravenously, subcutaneously, or intra-peritoneally (Alam and Schmidt 2002; Betarbet et al. 2000; Sherer et al. 2003c). Researchers have exposed various strains of rats to rotenone, including Wistar, Sprague-Dawley, and Lewis. Lewis rats show the most consistent responses to rotenone exposure and to another mitochondrial toxin, 3-nitropropionic acid (Betarbet et al. 2000; Ouary et al. 2000). The most extensively studied rotenone model of PD involves chronic exposure of Lewis rats to rotenone by implanting subcutaneous osmotic minipumps (Sherer et al. 2003c). Similar results are obtained whether rotenone is given intravenously or subcutaneously (Betarbet et al. 2000; Sherer et al. 2003c).

C. Rotenone Treatment Reproduces Many

Behavioral Symptoms of Parkinson Disease

PD is characterized by motor impairment including slowness of movement, tremor, postural problems, rigidity, and freezing behaviors. Investigators believe these symptoms stem from the depletion of striatal dopamine resulting from nigrostriatal dopaminergic degeneration (Wooten 1997). Most of the above behaviors were observed to varying extents in rotenone-treated animals. Rotenone-infused animals demonstrated reduced locomotor activity, hunched posture, and in some cases rigidity and freezing behavior (Betarbet et al. 2000; Sherer et al. 2003c). Specifically, rotenone-treated animals show decreased rearing, line crossing, and head dips in open field tests and increased catalepsy. In this study, behavioral deficits in rotenone-treated animals correlated with striatal dopamine loss (Alam and Schmidt, 2002). However, detailed studies on the effects of dopamine replacement on the behavioral deficits in rotenone-treated rats have not been conducted yet.

D. Selective Nigrostriatal Dopaminergic Degeneration in the Rotenone Model

One of the pathological hallmarks of PD is selective nigrostriatal dopaminergic degeneration. An initial study examining the effects of rotenone on the nigrostriatal dopaminergic system demonstrated that direct stereotaxic injection of rotenone into the medial forebrain bundle damaged the nigrostriatal dopaminergic system, marked by reduced dopamine levels in the striatum (Heikkila et al. 1985). Stereotaxic injections of rotenone did not cause selective dopaminergic depletion, as serotonin levels were reduced in striatum as well. However, only one dose of rotenone was administered so effects of lower doses of rotenone were unknown (Heikkila et al. 1985). Direct stereotaxic administration of rotenone also does not examine the effects of systemic rotenone infusion (and systemic mitochondrial impairment) on other brain regions. Never

III. The Rotenone Model of Parkinson Disease

Was this article helpful?

0 0
Unraveling Alzheimers Disease

Unraveling Alzheimers Disease

I leave absolutely nothing out! Everything that I learned about Alzheimer’s I share with you. This is the most comprehensive report on Alzheimer’s you will ever read. No stone is left unturned in this comprehensive report.

Get My Free Ebook


Post a comment