Duloxetine ameliorates valproic acid-induced hyperactivity, anxiety-like behavior, and social interaction deficits in zebrafish.

Syndromic autism spectrum disorders (ASDs) are characterized by impaired social communication and repetitive/stereotyped behaviors. Currently available therapeutic agents against ASD have limited efficacy. Thus, searching for novel and effective drugs ameliorating core symptoms, in particular social deficits, is of utmost importance. Duloxetine (DLX), an antidepressant that has been identified as an agonist mimetic for the cell adhesion molecule L1, exhibits beneficial functions in vitro and in vivo. Therefore, in this study, we focused on the rapid and persistent neuroprotective function of DLX following valproic acid (VPA)-triggered hyperactivity, anxiety-like behavior and social deficits in zebrafish. Embryonic exposure to VPA reduced survival in a dose- and time-dependent manner, delayed hatching, and also resulted in a significant number of malformed larvae. After initial dose-response experiments in zebrafish larvae, 10 µM VPA exposure between 0.33 and 4.5 days post fertilization (dpf) was identified as an effective concentration that led to an early and persistent ASD-like phenotype in zebrafish. ASD-like elevated acetylcholine esterase (AChE) activity and reduced Akt-mTOR signaling was observed in zebrafish whole brain. Acute administration of DLX (4.5-6 dpf) reduced the VPA-induced ASD-like phenotype in zebrafish larvae. Additionally, such early-life acute DLX treatment had long-term effects in ameliorating social impairments, hyperactivity, and anxiety-like behaviors through adulthood. This was accompanied by reduced AChE activity and by normalized Akt-mTOR signaling. Overall, DLX treatment showed a long-term therapeutic effect on autistic-like behaviors, and alteration of AChE activity and Akt-mTOR signaling were identified as crucial in the VPA-induced ASD zebrafish model.

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

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.