Cell therapy in the treatment of bipolar mania in an animal model: a proof of concept study

Abstract

Introduction The rationale of mesenchymal stem cells (MSCs) as a novel therapeutic approach in certain neurodegenerative diseases is based on their ability to promote neurogenesis. Hippocampal atrophy has been related to bipolar disorder (BD) in preclinical, imaging and postmortem studies. Therefore, the development of new strategies to stimulate the neurogenesis process in BD is crucial. Objectives To investigate the behavioral and neurochemical changes induced by transplantation of MSCs in a model of mania-like behavior induced by lisdexamfetamine dimesylate (LDX). Methods Wistar rats (n=65) received one oral daily dose of LDX (10 mg/kg) or saline for 14 days. On the 8th day of treatment, the animals additionally received intrahippocampal saline or MSC (1 µL containing 25,000 cells) or lithium (47.5 mg/kg) as an internal experimental control. Two hours after the last administration, behavioral and neurochemical analyses were performed. Results LDX-treated rats had increased locomotor activity compared to saline-saline rats (p=0.004), and lithium reversed LDX-related hyperactive behavior (p<0.001). In contrast, the administration of MSCs did not change hyperlocomotion, indicating no effects of this treatment on LDX-treated rats (p=0.979). We did not find differences between groups in BDNF levels (p>0.05) in the hippocampus of rats. Conclusion Even though these results suggest that a single intrahippocampal injection of MSCs was not helpful to treat hyperactivity induced by LDX and neither influenced BDNF secretion, we cannot rule out the possible therapeutic effects of MSCs. Further research is required to determine direct effects of LDX on brain structures as well as in other pathophysiological targets related to BD.

Andrographolide blocks 50-kHz ultrasonic vocalizations, hyperlocomotion and oxidative stress in an animal model of mania

“…LDX is a long-acting pro-drug of d-amphetamine employed in the therapeutic management of attention deficit/hyperactivity disorder (Ermer et al, 2016). LDX administration has also been used to mimic manic-like behavior in animals (Macêdo et al, 2013;de Souza et al, 2015;Eger et al, 2016;Wendler et al, 2016;Ascoli et al, 2017;Bristot et al, 2019). These manic-like behaviors were reversed or prevented by treatment with lithium or valproate (Macêdo et al, 2013;de Souza et al, 2015;Wendler et al, 2016;Ascoli et al, 2017;Bristot et al, 2019).…”

“…LDX administration has also been used to mimic manic-like behavior in animals (Macêdo et al, 2013;de Souza et al, 2015;Eger et al, 2016;Wendler et al, 2016;Ascoli et al, 2017;Bristot et al, 2019). These manic-like behaviors were reversed or prevented by treatment with lithium or valproate (Macêdo et al, 2013;de Souza et al, 2015;Wendler et al, 2016;Ascoli et al, 2017;Bristot et al, 2019). LDX administration also increases oxidative stress (Macêdo et al, 2013; de Souza et al, Data represent mean ± SD of the sum of USV emitted during the first 20s period of each 1-min interval of the 20-min test length.…”