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. 2024 Mar 15;16(3):403.
doi: 10.3390/pharmaceutics16030403.

Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study

George Jîtcă  1 , Zsolt Gáll  1 , Carmen-Maria Jîtcă  2 , Mădălina-Georgiana Buț  3 , Erzsébet Májai  4
Affiliations

Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study

George Jîtcă et al. Pharmaceutics. .

Abstract

A particular attribute of the brain lies in the ability to learn, acquire information from the environment, and utilize the learned information. Previous research has noted that various factors (e.g., age, stress, anxiety, pathological issues), including antipsychotic medications, affect the brain and memory. The current study aimed to reveal the effects of chronic metformin treatment on the cognitive performance of rats and on commonly measured markers for oxidative stress. Wistar male rats (n = 40) were randomly divided into four groups: CTR (n = 10)-control group, METF (n = 10)-animals receiving metformin 500 mg/kg, HAL (n = 10)-animals receiving haloperidol 2 mg/kg, and HALMETF (n = 10)-animals receiving haloperidol 2 mg/kg and metformin 500 mg/kg. The medication was administered daily by oral gavage for 40 days. Memory and learning were assessed using the Morris Water Maze (MWM) test. At the end of the MWM, the rodents were decapitated under anesthesia, and the brain and blood samples were assayed by liquid chromatography for markers of oxidative stress (malondialdehyde, MDA, reduced/oxidized glutathione ratio, GSH/GSSG). The quantification of brain-derived neurotrophic factor (BDNF) was performed using the conventional sandwich ELISA technique. In the HALMETF group, metformin attenuated the negative effects of haloperidol. Brain and plasma MDA levels increased in the HAL group. Brain and plasma GSH/GSSG ratios and BDNF levels did not reveal any differences between groups. In conclusion, metformin treatment limits the deleterious cognitive effects of haloperidol. The effect on oxidative stress markers may also point toward an antioxidant-like effect of metformin, but this needs further tests for confirmation.

Keywords: cognition; glutathione; malondialdehyde; metformin; oxidative stress.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of the chronology of the experimental design.
Figure 2
Figure 2
The escape latency through the four days of practice. Values displayed are means ± SEM. Statistically significant differences compared to the CTR group (n = 10) are noted with * p < 0.05, ** p < 0.01, *** p < 0.001. Statistically significant differences compared to the METF group (n = 10) are noted with # p < 0.05, ## p < 0.01, ### p < 0.001, #### p < 0.0001. Statistically significant differences compared to the HALMETF group (n = 10) are noted with + p < 0.05, ++ p < 0.01.
Figure 3
Figure 3
The distances covered to the rescue platform in the four quadrants, during the four days of training. Values displayed are means ± SEM. Statistically significant differences are noted with * p < 0.05, ** p < 0.01, and *** p < 0.001.
Figure 4
Figure 4
The effect of HAL and METF treatment on swimming speeds during the four days of training. Values displayed are means ± SEM. Statistically significant differences compared to the CTR group are noted with ** p < 0.01, **** p < 0.0001. Statistically significant differences compared to the METF group are noted with # p < 0.05, ## p < 0.01, ### p < 0.0001. Statistically significant differences compared to the HALMETF group are noted with + p < 0.05, ++ p < 0.01.
Figure 5
Figure 5
Differences in entries frequency in Q4 (A) and swimming speed (B). Values displayed are means ± SEM. Statistically significant differences compared to the CTR group are noted with **** p < 0.0001. Statistically significant differences compared to the METF group are noted with ### p < 0.001, #### p < 0.0001. Statistically significant differences compared to the HALMETF group are noted with ++ p < 0.01, +++ p < 0.001.
Figure 6
Figure 6
The distances traveled by the four groups in each quadrant. Values displayed are means ± SEM. Statistically significant differences compared to the CTR group are noted with * p < 0.05, ** p < 0.01, **** p < 0.0001. Statistically significant differences compared to the METF group are noted with # p < 0.05, ## p < 0.01, ### p < 0.001. Statistically significant differences compared to the HALMETF group are noted with + p < 0.05, +++ p < 0.001.
Figure 7
Figure 7
The effect of chronic treatment on time spent in the target quadrant, Q4. Values displayed are means ± SEM.
Figure 8
Figure 8
Effects of haloperidol and metformin on plasma (A) and brain (B) malondialdehyde (MDA) levels. Values displayed are means ± SEM for plasma MDA concentration and median (IQR) for brain MDA concentrations; * p < 0.05, ** p < 0.01.
Figure 9
Figure 9
Effects of haloperidol and metformin on plasma (A) and brain (B) GSH/GSSG ratios. Values displayed are median (IQR).
Figure 10
Figure 10
Plasmatic levels of Brain Derived Neurotrophic Factor (BDNF) among the experimental groups of rats. Values displayed are means ± SEM.
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