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. 2024 Nov 27;50(1):34.
doi: 10.1007/s11064-024-04295-6.

Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral, Biochemical, and Mitochondrial Alterations

Anushka Vashishth  1 , Garima Sharma  1 , Ankan Sarkar  1 , Monika Kadian  1   2 , Manish Jain  3 , Anil Kumar  4
Affiliations

Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral, Biochemical, and Mitochondrial Alterations

Anushka Vashishth et al. Neurochem Res. .

Abstract

Chronic fatigue stress (CFS) is a multisystem disorder which exhibits multiple signs of neurological complications like brain fog, cognitive deficits and oxidative stress with no specific treatment. Doxophylline, a non-selective phosphodiesterase inhibitor (PDEI), has anti-inflammatory properties with enhanced blood-brain barrier penetration and tissue specificity. We have evaluated the neuroprotective potential of doxophylline in a murine model of forced swim test (FST) induced CFS and in H2O2 (hydrogen peroxide) induced oxidative stress in PC12 cells. An FST model to induce a state of CFS in mice was induced by forcing them to swim daily for 6 min for 15 days. The drug was administered daily 30 min prior to FST. The immobility period was compared for day 1 and day 15. Animals were sacrificed on day 16 for biochemical, mitochondrial, and histopathological estimations in the brain. Cytotoxicity assay, reactive oxygen species (ROS) and nuclear morphology determination were carried out in PC12 cells. A significant increase in immobility has been observed on the 15th day in CFS-induced mice compared to doxophylline treated group. Neurobehavioral studies revealed hypo locomotion, anxiety, motor incoordination, and memory deficit. Biochemical analysis showed a significant change in oxidative stress markers (superoxide dismutase (SOD), reduced glutathione (GSH), catalase, lipid peroxidation (LPO) and nitrite levels) and acetylcholinesterase enzyme activity (AChE) in brain homogenates. Doxophylline pre-treatment protects against these impairments. In PC12 cell lines, doxophylline exhibits alleviation against H2O2-induced oxidative stress, intracellular ROS generation, and changes in nuclear morphology. Doxophylline could be promising and possess therapeutic potential in CFS treatment. Further research is needed to test if doxophylline can be repurposed for neurological disorders.

Keywords: Chronic fatigue stress; Doxophylline; Neurological complications; Oxidative stress; ROS.

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Conflict of interest statement

Declarations. Ethics Approval: All protocols for animal experimentation were approved by Institutional Animal Ethics Committee (IAEC) of Panjab University, Chandigarh-160014, India against approval no. (PU/45/99/CPCSEA/IAEC/2022/706) and conducted in accordance with CCSEA guidelines for use & care of experimental animals. Competing Interests: The authors declare no competing interests.

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