Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish

Abstract

Besides several endogenous elements, exogenous factors, including exposure to pesticides, have been recognized as putative factors contributing to the onset and development of neurodegenerative diseases, including Parkinson's disease (PD). Considering the availability, success rate, and limitations associated with the current arsenals to fight PD, there is an unmet need for novel therapeutic interventions. Therefore, based on the previously reported beneficial functions of the L1 cell adhesion molecule, we hypothesized that L1 mimetic compounds may serve to neutralize neurotoxicity triggered by the pesticide paraquat (PQ). In this study, we attempt to use PQ for inducing PD-like pathology and the L1 mimetic compounds phenelzine sulfate (PS) and tacrine (TC) as potential candidates for the amelioration of PD symptoms using zebrafish as a model system. Administration of PQ together with the L1 mimetic compounds PS or TC (250 nM) improved survival of zebrafish larvae, protected them from locomotor deficits, and increased their sensorimotor reflexes. Moreover, application of PQ together with PS (500 nM) or TC (1000 nM) in adult zebrafish counteracted PQ-induced toxicity, maintaining normal locomotor functions and spatial memory in an open field and T-maze task, respectively. Both L1 mimetic compounds prevented reduction in tyrosine hydroxylase and dopamine levels, reduced reactive oxygen species (ROS) generation, protected against impairment of mitochondrial viability, improved the antioxidant enzyme system, and prevented a decrease in ATP levels. Altogether, our findings highlight the beneficial functions of the agonistic L1 mimetics PS and TC by improving several vital cell functions against PQ-triggered neurotoxicity.

The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

“…Behavioral-wise, paraquat reduces locomotor activity of zebrafish, indicated by decreased swimming distance and velocity ( Wang et al, 2018 ). This finding agrees with Joseph et al (2020) , who documented an increase in the number of freezing bouts and freezing durations of zebrafish after paraquat administration. Moreover, the same study also found that paraquat impairs the process of acquiring and consolidating spatial memory.…”

“…Redox imbalance caused by the increased mitochondrial ROS production causes oxidative stress and damages mitochondrial respiration (Bastías-Candia et al, 2019). Supporting this, Joseph et al (2020) reported that paraquat exposure to zebrafish larvae reduced mitochondrial viability and obstructed the production of ATP. Interestingly, paraquat is also found to activate nuclear factor-kappa B (NFκB) that results in DNA fragmentation and TLR4/NFκB-mediated neuroinflammation (Feng et al, 2019;.…”

“…Indeed, the most prominent cause of paraquat-induced neurotoxicity is the elevated production of superoxide and hydrogen peroxide ( Wang et al, 2018 ). Additionally, though paraquat toxicity triggers mitochondrial dysfunction, but unlike MPTP, paraquat is less likely to inhibit the mitochondrial complex I activity ( Joseph et al, 2020 ).…”

“…It is striking to note that, like the rodent model, optimized and standardized behavioral assessments are needed to increase the accuracy and reliability of the zebrafish model (Vaz et al, 2018), in parallel with its advancing application in PD studies. Nunes et al, 2017;Wang et al, 2018;Bastías-Candia et al, 2019;Feng et al, 2019;Vaccari et al, 2019;Joseph et al, 2020 Rotenone -Inhibition of the mitochondrial complex I activity -Increased ROS production -Reduced ATP production α-synuclein aggregation -Reduced dopamine level -Reduced mitochondrial calcium level -Increased activation of microglia and pro-inflammatory proteins -Motor impairments (reduced swimming speed, reduced distance traveled) -Anxiety -Depression -Olfactory dysfunction Gao et al, 2013;Wang et al, 2017;Lv et al, 2019;Hijaz and Volpicelli-Daley, 2020;Ramli et al, 2020;Ünal et al, 2020;Yurtsever et al, 2020 Anichtchik et al, 2008;Sallinen et al, 2010;Xi et al, 2010;Priyadarshini et al, 2013 Sheng et al, 2010;Prabhudesai et al, 2016;Sheng et al, 2018;Seegobin et al, 2020 neurotoxin inductions and PD-associated gene mutations on the zebrafish model of PD.…”

Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics

“…14,17 L1 mimetics stimulated repair not only in mice but also in zebrafish, where they improved recovery after spinal cord injury, 16 remyelination after demyelination (Hae-Chul Park, personal communication), and resistance to a pesticide. 47 Three L1 mimetic compounds, one of them (duloxetine) FDA approved, indeed, enhanced neuronal migration and survival, neurite outgrowth of cerebellar neurons, and process formation of Schwann cells in cell culture. In a previous study, we have shown that the L1 mimetic compounds also stimulate neurite outgrowth from spinal motor neurons, dorsal root ganglion neurons and cortical neurons as well as proliferation and migration of Schwann cells and in vitro myelination.…”