Dyskinesia

Dyskinesias/choreas are excessive involuntary movements, ranging from essential tremor to disabling choreas. 

One of the most common and most readily studied dyskinesias is induced by L-DOPA treatment in Parkinson's disease. Extracellular guanosine/guanine signaling is directly implicated in L-DOPA induced dyskinesia: PMID 32426479.

VMAT2 inhibitors are recommended for treatment of severe dyskinesia, including tardive dyskinesia and Huntington's chorea.

Reserpine, a VMAT2 inhibitor, acutely decreases guanosine concentrations and acutely increases guanine concentrations in the Parkinson's-implicated portion of the brain, the substantia nigra: PMID 9510422. L-DOPA demonstrates similar effects on guanosine and guanine, but to a lesser extent. This may reflect activation of the enzyme that converts guanosine to guanine, purine nucleoside phosphorylase (PNP).  IMG

Treatments for dyskinesia including reserpine, tetrabenazine (the active metabolite of prodrug valbenazine) share an apparent active site that is also shared with oxidopamine and, to a lesser degree, L-DOPA.  IMG

Repeated reserpine, tetrabenazine, and oxidopamine administrations have been used to model dystonias: catatonia: PMID 4964216 and progressive Parkinsonism: PMID 25726735. 

Excess involuntary movement in dyskinesia and the involuntary lack of movement in dystonia may reflect a single underlying cause. IMG

The most widely known example of dyskinesia is likely the portrayal in Awakenings of the transition from a dystonic state treated with L-DOPA, followed by diskinesia and eventual relapse into dystonia.

Zaprinast improved L-DOPA-induced dyskinesia in hydroxdopamine-lesioned rats PMID 18717735, suggesting that related PDE5 inhibitors (sildenafil, etc.) may be helpful in treating dyskinesia, a possibility mentioned in PMID 30363412. In overdose, sildenafil has been associated with dyskinesia PMID 20040342, suggesting that the relationship between cGMP and dyskinesia is not direct. 

Acetazolamide + thiamine PMID 9169964

IMG