Recent Advances in the cause and treatment of Parkinson ：在帕金森的原因和治疗的最新进展.ppt

Symptomatic treatments for Parkinson disease Drug treatment of Parkinson’s disease L-dopa Decarboxylase inhibitors – carbidopa, benserazide MAO-B inhibitors – selegiline, rasagiline COMT inhibitors – entacapone, tolcapone Combination forms – Stalevo Controlled release – Sinemet CR Dispersible – Madopar dispersible Liquid formulations – L-dopa methyl ester Intraduodenal administration - DuoDopa Ropinirole Pramipexole Pergolide Bromocriptine Cabergoline Extended release – Requip XL Transdermal administration – NeuPro Subcutaneous infusion - apomorphine Safinamide Reversible MAOB inhibitor May have Na-channel, anti-glutamatergic activity Once daily 50-100mg Adjunct to levodopa (+) or dopamine agonist Reduces OFF-time, improves ON-time without increasing troublesome dyskinesia. Non-dopaminergic approaches to the treatment of Parkinson’s disease Motor symptoms – amantadine, anticholinergics Dementia – cholinesterase inhibitors Psychosis – atypical antipsychotics Neuropsychiatric – anxiolytics, antidepressants Somnolence – modafinil Autonomic signs – mineralocorticosteroids, oxybutyninn Neuroprotection Slowing the course of Parkinson disease Potential therapeutic targets Mitochondria: CoQ +/- vit E, creatine, PGC-1α, rasagiline, exenetide Anti-oxidants: Fe-chelators, inosine LRRK2 kinase inhibitors Growth factor stimulants: GDNF, BDNF Autophagy/mitophagy stimulants: rapamycin Protein disaggregation Calcium channel modulators: isradipine SNCA modulators GBA enhancers – chaperones Schapira Lancet 2014 The GCase - alpha-synuclein connection ↓ TOXICITY GBA siRNA, CBE, GBA-KO mice, PD brain SNCA o/e cells, PD triplication cells, PD brain AAV-GBA Schapira Lancet 2014 Schapira Gegg PNAS 2013 GCase-alpha-synuclein as a target for PD Hypothesis Increasing GCase activity will reduce SNCA levels and slow the progression of PD This will be relevant to those with and without PD Proof of principle control/PD control/PD+ GD GD+ P