Assessing the Neurotoxicity of a Sub-Optimal Dose of Rotenone in Zebrafish (Danio rerio) and the Possible Neuroactive Potential of Valproic Acid, Combination of Levodopa and Carbidopa, and Lactic Acid Bacteria Strains

Abstract

Background: Parkinson’s disease (PD) is an enigmatic neurodegenerative disorder that is currently the subject of extensive research approaches aiming at deepening the understanding of its etiopathophysiology. Recent data suggest that distinct compounds used either as anticonvulsants or agents usually used as dopaminergic agonists or supplements consisting of live active lactic acid bacteria strains might alleviate and improve PD-related phenotypes. Methods: This is why we aimed to elucidate how the administration of rotenone (ROT) disrupts homeostasis and the possible neuroactive potential of valproic acid (VPA), antiparkinsonian agents (levodopa and carbidopa – LEV+CARB), and a mixture of six Lactobacillus and three Bifidobacterium species (PROBIO) might re-establish the optimal internal parameters. Results: ROT causes significant changes in the central nervous system (CNS), notably reduced neurogenesis and angiogenesis, by triggering apoptosis, reflected by the increased expression of PARKIN and PINK1 gene(s), low brain dopamine (DA) levels, and as opposed to LRRK2 and SNCA compared with healthy zebrafish. VPA, LEV/CARB, and PROBIO sustain neurogenesis and angiogenesis, manifesting a neuroprotective role in diminishing the effect of ROT in zebrafish. Interestingly, none of the tested compounds influenced oxidative stress (OS), as reflected by the level of malondialdehyde (MDA) level and superoxide dismutase (SOD) enzymatic activity revealed in non-ROT-exposed zebrafish. Overall, the selected concentrations were enough to trigger particular behavioral patterns as reflected by our parameters of interest (swimming distance (mm), velocity (mm/s), and freezing episodes (s)), but sequential testing is mandatory to decipher whether they exert an inhibitory role following ROT exposure. Conclusions: In this way, we further offer data into how ROT may trigger a PD-related phenotype and the possible beneficial role of VPA, LEV+CARB, and PROBIO in re-establishing homeostasis in Danio rerio.

Lactiplantibacillus (Lactobacillus) plantarum as a Complementary Treatment to Improve Symptomatology in Neurodegenerative Disease: A Systematic Review of Open Access Literature

“…A total of 17 studies were conducted using different animal models. Of these, 4 focused on AD [ 95 , 96 , 97 , 98 ] ( n = 4); 7 focused on PD [ 99 , 100 , 101 , 102 , 103 , 104 , 105 ] ( n = 7); 1 analyzed MS [ 106 ], ( n = 1); 3 studied oxidative stress [ 107 , 108 , 109 ] ( n = 3); 1 on cognitive impairment and oxidative stress [ 110 ] ( n = 1); and 1 on neurodegenerative process [ 111 ] ( n = 1). All of them addressed the intervention with Lactobacillus plantarum or Lactiplantibacillus plantarum for the improvement of symptoms associated with neurodegenerative pathologies.…”

“…Another recent study was carried out in 2022 by Ilie et al In this research, an adult zebrafish model (wild-type AB; WT, genetic line) with ROT-rotenone-induced motor impairment was used [ 105 ]. Then, the administration of different compounds was included to study their impact on these deficits.…”

“…Evidence suggests that the use of Lactiplantibacillus plantarum significantly reduces motor deficits. It also reduces levels of inflammatory factors and maintains neuroprotective effects on dopaminergic neurons, both in vivo and in vitro [ 99 , 100 , 101 , 102 , 103 , 104 , 105 ].…”

“…Evidence suggests that the use of Lactiplantibacillus plantarum significantly reduces motor deficits. It also reduces levels of inflammatory factors and maintains neuroprotective effects on dopaminergic neurons, both in vivo and in vitro [99][100][101][102][103][104][105] Consumption of this probiotic improved motor function, showing an increase in horizontal and vertical activity of mice as opposed to the more limited activity of the vehicletreated mice (p < 0.01 vs. TMEV-mice). In addition, it was shown that mice treated with Vivomixx underwent subtle changes in the composition of the gut microbiota.…”

Temperature- and chemical-induced neurotoxicity in zebrafish

“…Notable among these genes are the Autophagy-related ( atg ) genes, such as atg3 , atg5 ( Li et al, 2018 ; Li et al, 2020 ; Li et al, 2021 ), the Unc-51 like autophagy activating kinase ( ulk ) genes, including ulk1b ( Li et al, 2021 ), ulk2 ( Ji et al, 2021 ). Other critical genes include becn1 ( Li et al, 2018 ; Li et al, 2020 ; Li et al, 2021 ) genes, the map1lc3a (Microtubule-associated protein 1A/1B-light chain 3) gene ( Liu et al, 2019 ), and finally the pink1 (PTEN-induced putative kinase 1) ( Li et al, 2020 ; Li et al, 2021 ; Yang et al, 2022 ) and parkin ( Li et al, 2021 ; Wang et al, 2021 ; Yang et al, 2022 ; Ilie et al, 2022 ) genes, which are involved in mitophagy ( Supplementary Table S2 ). For example, exposure to silica nanoparticles has been found to increase the expression of ulk1b , beclin 1 , atg5 , pink and parkin ( Li et al, 2020 ), while lead exposure resulted in increased ulk1b expression and decreased beclin 1 , atg5 , and lc3 expression ( Ji et al, 2021 ).…”