Small molecules to perform big roles: The search for Parkinson's and Huntington's disease therapeutics

Journal
Frontiers in Neuroscience
ISSN
1662-453X
Date Issued
2023
Author(s)
Rodrigo Pérez-Arancibia
Marisol Cisternas-Olmedo
Denisse Sepúlveda
Paulina Troncoso-Escudero
Rene L. Vidal
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85146864811
WoS ID
WOS:000918007300001
DOI
URL
URL Institutional Repository
Abstract
<jats:p>Neurological motor disorders (NMDs) such as Parkinson's disease and Huntington's disease are characterized by the accumulation and aggregation of misfolded proteins that trigger cell death of specific neuronal populations in the central nervous system. Differential neuronal loss initiates the impaired motor control and cognitive function in the affected patients. Although major advances have been carried out to understand the molecular basis of these diseases, to date there are no treatments that can prevent, cure, or significantly delay the progression of the disease. In this context, strategies such as gene editing, cellular therapy, among others, have gained attention as they effectively reduce the load of toxic protein aggregates in different models of neurodegeneration. Nevertheless, these strategies are expensive and difficult to deliver into the patients' nervous system. Thus, small molecules and natural products that reduce protein aggregation levels are highly sought after. Numerous drug discovery efforts have analyzed large libraries of synthetic compounds for the treatment of different NMDs, with a few candidates reaching clinical trials. Moreover, the recognition of new druggable targets for NMDs has allowed the discovery of new small molecules that have demonstrated their efficacy in pre-clinical studies. It is also important to recognize the contribution of natural products to the discovery of new candidates that can prevent or cure NMDs. Additionally, the repurposing of drugs for the treatment of NMDs has gained huge attention as they have already been through clinical trials confirming their safety in humans, which can accelerate the development of new treatment. In this review, we will focus on the new advances in the discovery of small molecules for the treatment of Parkinson's and Huntington's disease. We will begin by discussing the available pharmacological treatments to modulate the progression of neurodegeneration and to alleviate the motor symptoms in these diseases. Then, we will analyze those small molecules that have reached or are currently under clinical trials, including natural products and repurposed drugs.</jats:p>
Subjects
drug repurposing

; 

huntington's disease

; 

natural products

; 

parkinson's disease

; 

pharmacological therapy

; 

small molecules

; 

5,7 dichloro 2 dimethylaminomethyl 8 quinolinol

; 

amantadine

; 

ambroxol

; 

cannabinoid

; 

catechin

; 

clenbuterol

; 

cryopyrin

; 

curcumin

; 

deferiprone

; 

dronabinol

; 

entacapone

; 

fenofibrate

; 

isradipine

; 

levodopa

; 

mesdopetam

; 

metformin

; 

nabilone

; 

pramipexole

; 

rasagiline

; 

resveratrol

; 

salbutamol

; 

selegiline

; 

selisistat

; 

sinecatechins

; 

tetrabenazine

; 

tolcapone

; 

antiinflammatory activity

; 

antioxidant activity

; 

cell therapy

; 

clinical trial (topic)

; 

drug bioavailability

; 

drug efficacy

; 

drug mechanism

; 

drug repositioning

; 

food and drug administration

; 

gene editing

; 

gold standard

; 

human

; 

huntington chorea

; 

motor dysfunction

; 

nerve cell plasticity

; 

nerve degeneration

; 

neuroprotection

; 

neurotransmission

; 

non insulin dependent diabetes mellitus

; 

parkinson disease

; 

phase 1 clinical trial (topic)

; 

phase 2 clinical trial (topic)

; 

phase 3 clinical trial (topic)

; 

protein aggregation

; 

review

; 

therapy effect