TJ wrote the manuscript. symptoms using zebrafish like a model system. Administration of PQ together with the L1 mimetic compounds PS or TC (250 nM) improved survival of zebrafish larvae, safeguarded them from locomotor deficits, and improved their sensorimotor reflexes. Moreover, software of PQ together with PS (500 nM) or TC (1000 nM) in adult zebrafish counteracted PQ-induced toxicity, keeping normal locomotor functions and spatial memory space in an open field and T-maze task, respectively. Both L1 mimetic compounds prevented reduction in tyrosine hydroxylase and dopamine levels, reduced reactive oxygen IPA-3 species (ROS) generation, safeguarded 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. and models of PD (Lima et al., 2014; Jahromi et al., 2015). Concerning restorative interventions against PD, existing treatments provide temporary symptomatic alleviation without repairing mitochondrial function or slowing disease progression (Schapira et al., 2014), and compounds shown to efficiently protect DA neurons from 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced toxicity, and Biochemical Co., Ltd., Shanghai, China), PS (C8H14N2O4S, 99.98%, Cat no. HY-B1018A, MedChemExpress, NJ, United States), and TC (C13H17ClN2O, 98.70%, Cat no. HY-B2244, MedChemExpress, NJ, United States) were prepared in distilled water, and the exposure solutions were prepared by diluting stock solutions into E3 press to achieve the desired concentrations. Open in a separate window Number 1 Experimental strategy, survival analysis, and behavioral guidelines in zebrafish larvae treated with paraquat (PQ) and L1 mimetics. (A) Schematic representation of the experimental plan for zebrafish larvae treatment with PQ and L1 mimetics. At 3 dpf, morphologically normal larvae were treated with the indicated concentrations of PQ and at the same time exposed to phenelzine sulfate (PS) and tacrine (TC) until 7 dpf. At 5 and 7 dpf, a behavioral evaluation was performed while survival under different treatment conditions was investigated until 7 dpf. (B) Survival analysis of zebrafish larvae after treatment with ( 0.05, ** 0.01, and *** 0.001 PQ control group. (C) Spontaneous movement analysis of zebrafish larvae under treatment with PQ (500 M) and L1 mimetics (250 nM) from 3 dpf until measurements (5 dpf). ( 0.001 PQ control group GNAS and PQ PQ + PS or PQ + TC organizations; ns, not significant PS or TC control group; ( 0.001 PQ control group, ## 0.01, and ### 0.001 PQ PQ + PS and PQ + TC groups; ns, not significant PS or TC IPA-3 control group. Data are offered as mean SEM of IPA-3 two self-employed experiments (= 24 larvae/group/experiment) and analyzed by one-way analysis of ANOVA using Tukeys test. For survival analysis, hatched larvae at 3 dpf without apparent abnormalities were exposed to PQ (10C5000 M) and L1 mimetics (PS and TC) inside a six-well plate (Aircraft Biofil, Guangzhou, China) (24 larvae/3 ml/well) until 7 dpf. The exposure tests were carried out following a OECD recommendations (OECD, 1992), the concentration range of PQ was selected based on earlier studies (Imamura et al., 2011; Wang et al., 2018; Pinho et al., 2019), and for L1 mimetics (250 nM), concentration was selected for both mimetics based on their beneficial role in earlier studies (Li et al., 2018; Sahu et al., 2018). In order to determine the effect of different treatments on the survival of zebrafish larvae, each concentration (10C5000 M) of PQ only and PQ in the presence of L1 mimetics (PS or TC) at 5 and 7 dpf were individually compared and statistically analyzed by one-way analysis of variance (ANOVA) using Tukeys test. For evaluation of behavioral experiments, such as spontaneous swimming and sensorimotor reflexes, zebrafish larvae.