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5α-reductase inhibitors ameliorate L-DOPA-induced dyskinesia

 

Parkinson’s disease is a neurodegenerative disorder, characterised by death of dopaminergic neurons in midbrain and locomotor abnormalities. The conventional therapy involves L-DOPA, a brain-penetrant dopamine precursor. However, its long-term administration frequently leads to drug-induced involuntary movements and dystonia. These adverse effects are known as L-DOPA-induced dyskinesia (LID) and are a consequence of excessive stimulation of dopamine D1 receptors.

 

It has been demonstrated that inhibitors of a rate-limiting enzyme in neurosteroid synthesis, 5α-reductase (5AR), can prevent key events in the appearance of LID. The 5AR inhibitors re-establish balance in the neurosteroidogenic pathway as well as normal D1 receptor signalling.

 

A study from 2018 compared the effects of two 5AR inhibitors from Carbosynth, finasteride and dutasteride, in a rodent model for Parkinson’s disease.

 

Finasteride

Dutasteride

Inhibitory potency

(IC50)

5AR1 - 360 nM

5AR2 - 69 nM

5AR1 - 6 nM

5AR2 - 7 nM

Inhibition type

Irreversible

Irreversible

Half-life

6-8 hours

5-6 weeks

Table 1: Properties of two 5AR inhibitors used in the study.

 

Although both compounds reduced LID, dutasteride resulted to be more effective since it ameliorated dyskinesia at lower doses than finasteride. Moreover, dutasteride had no impact on the therapeutic effects of L-DOPA. This study also suggests that favourable anti-dyskinetic profile of dutasteride relies on its high affinity to the 5AR1 isoform.

 

For more details, read the original paper published in Neurobiology of Disease: Fanni et al., 2018.

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