Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Abstract

Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

“…With a prevalence of 1-2 per 1000 in unselected populations and of 1% in the population above 60 years, PD represents the most frequent movement disorder and the second most frequent neurodegenerative disease of the CNS [43]. While less than 10% of PD cases are familial, the majority of PD cases are sporadic and may depend on a combination of multiple factors, including age, gender, genetic, and environmental factors [44]. Male sex and increasing age may be independent risk factors, whereas smoking and coffee drinking seem to be protective factors [45].…”

“…About 30% of the familial and 3-5% of the sporadic PD cases are monogenic forms that derive from a single mutation in a gene and that can be inherited dominantly, such as SNCA (PARK1 = 4), and LRRK2 (PARK8) or recessively, such as Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), and ATP13A2 (PARK9) [46]. Moreover, it seems that all familial PD cases are correlated with mutations in genes directly or indirectly involved in mitochondrial dysfunction [44].…”

“…In cases where primary treatment is not effective, deep brain stimulation may be a potential therapeutic strategy [45]. Another interesting possible approach to treat PD is represented by nigral cell transplantation [44]. Moreover, a promising treatment option seems to rely on gene therapy aimed at correcting PD-related genes or at increasing neurotrophic factors, by using CRISPR technology, viral vectors, small interfering RNA (siRNA), or microRNA (miRNA) [44].…”

“…Another interesting possible approach to treat PD is represented by nigral cell transplantation [44]. Moreover, a promising treatment option seems to rely on gene therapy aimed at correcting PD-related genes or at increasing neurotrophic factors, by using CRISPR technology, viral vectors, small interfering RNA (siRNA), or microRNA (miRNA) [44]. Promising results in reducing the risks of PD development have been observed with natural products such as green tea, coffee, and cotinine, a nicotine metabolite [44].…”

“…Moreover, a promising treatment option seems to rely on gene therapy aimed at correcting PD-related genes or at increasing neurotrophic factors, by using CRISPR technology, viral vectors, small interfering RNA (siRNA), or microRNA (miRNA) [44]. Promising results in reducing the risks of PD development have been observed with natural products such as green tea, coffee, and cotinine, a nicotine metabolite [44]. Considering the multifactorial etiology and the different subtypes of PD, tailored approaches of precision medicine are needed [44].…”