The cross-hemispheric nigrostriatal pathway prevents the expression of levodopa-induced dyskinesias

NEUROBIOLOGY OF DISEASE

卷:159

Article

Iyer, Vishakh^1,5  Venkiteswaran, Kala¹  Savaliya, Sandip²  Lieu, Christopher A.¹  Handly, Erin¹  Gilmour, Timothy P.³  Kunselman, Allen R.⁴  Subramanian, Thyagarajan¹ 

[1] Penn State Univ, Dept Neurol & Neural & Behav Sci, Coll Med, Hershey, PA 17033 USA

[2] Penn State Univ, Dept Neurosurg, Coll Med, Hershey, PA 17033 USA

[3] John Brown Univ, Dept Elect Engn, Siloam Springs, AR USA

[4] Penn State Univ, Dept Publ Hlth Sci, Coll Med, Hershey, PA 17033 USA

[5] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA

关键词: Dyskinesia;    Dopamine;    Levodopa;    Parkinson's disease;    Interhemispheric;    Rat;   

DOI  :  10.1016/j.nbd.2021.105491

来源: Elsevier

【 摘 要 】

Parkinson's disease (PD) is a neurodegenerative movement disorder that is routinely treated with levodopa. Unfortunately, long-term dopamine replacement therapy using levodopa leads to levodopa-induced dyskinesias (LID), a significant and disabling side-effect. Clinical findings indicate that LID typically only occurs following the progression of PD motor symptoms from the unilateral (Hoehn and Yahr (HY) Stage I) to the bilateral stage (HY Stage II). This suggests the presence of some compensatory interhemispheric mechanisms that delay the occurrence of LID. We therefore investigated the role of interhemispheric connections of the nigrostriatal pathway on LID expression in a rat model of PD. The striatum of one hemisphere of rats was first injected with a retrograde tracer to label the ipsi- and cross-hemispheric nigrostriatal pathways. Rats were then split into groups and unilaterally lesioned in the striatum or medial forebrain bundle of the tracer-injected hemisphere to induce varying levels of hemiparkinsonism. Finally, rats were treated with levodopa and tested for the expression of LID. Distinct subsets emerged from rats that underwent the same lesioning paradigm based on LID. Strikingly, nondyskinetic rats had significant sparing of their cross-hemispheric nigrostriatal pathway projecting from the unlesioned hemisphere. In contrast, dyskinetic rats only had a small proportion of this cross-hemispheric nigrostriatal pathway survive lesioning. Crucially, both non-dyskinetic and dyskinetic rats had nearly identical levels of ipsi-hemispheric nigrostriatal pathway survival and parkinsonian motor deficits. Our data suggest that the survival of the cross-hemispheric nigrostriatal pathway plays a crucial role in preventing the expression of LID and represents a potentially novel target to halt the progression of this devastating side-effect of a common anti-PD therapeutic.