Strategies for the modulation of mitochondrial metabolism and activity in the treatment of neurodegenerative diseases: A systematic review and meta-analysis.

Neurodegenerative diseases (NDDs) are currently raising their prevalences and new preclinical low-cost investigations of drug design are urging. NDDs encompass a wide range of disorders, including Alzheimers, Parkinsons, ALS and others, many of which share mitochondrial dysfunction as a common pathological feature. As such, targeting mitochondrial metabolism has emerged as a promising therapeutic strategy. However, while rodent models are widely used in NDD research, they are costly and time-consuming, raising the need to consider other alternatives to accelerate the search for novel therapies. In this line, zebrafish (Danio rerio) have gained outstanding popularity as a valuable option. This systematic review aims to provide an extensive overview about the current strategies that use zebrafish assays to investigate modulations of mitochondrial function as new therapies against NDDs. The review was performed following an electronic search of different databases (PubMed, Embase, Scopus and Web of Science) after the PRISMA procedure. Articles published in the English language were identified and screened based on the keywords used: mitochondrial metabolism, therapy, neurodegenerative diseases and zebrafish. Following 176 entries, exclusion criteria reduced the record to 34 final studies. Overall, we found that these studies investigate 37 compounds: 24 natural, 6 semisynthetic, 5 synthetic and 2 compounds of not-determined origin; to ameliorate 9 prevalent diseases: ARSACS, Alzheimers, Parkinsons, Huntingtons diseases, Leigh and Wolfram syndromes, Amyotrophic lateral sclerosis, Limb - girdle muscular dystrophy 2G and hyperglycemia-associated amnesia. Additionally, a meta-analysis of these compounds and their gene interactions provides insights into their mechanisms of action and advances our understanding of NDDs, and furnishes us with a powerful tool to predictive potential new drugs or to repurpose existing ones. To conclude, this systematic review suggests that zebrafish have become an effective model for screening potential drugs for NDDs with symptomatology difficult to replicate in rodent models. Moreover, the use of computational tools is also emphasized as a promising strategy to guide therapeutic discovery more efficiently, reducing both time and costs, in developing treatments for NDDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/710294v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@18893a1org.highwire.dtl.DTLVardef@1943a12org.highwire.dtl.DTLVardef@709146org.highwire.dtl.DTLVardef@51a488_HPS_FORMAT_FIGEXP M_FIG C_FIG