Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral,... 2024 Kumar et al

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

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.

Paywall, https://link.springer.com/article/10.1007/s11064-024-04295-6

 

"a state of CFS in mice was induced by forcing them to swim daily for 6 min for 15 days"

distressing and pointless

 

They don't even say what 'chronic fatigue stress' is supposed to be. It sounds like something they made up for the purpose of the experiment.

 

As the reference list has a lot of ME/CFS and Long Covid papers, and this sort of animal model has been used before for "chronic fatigue syndrome", I have assumed they think they are investigating what we would call ME/CFS, but with no access to the paper I can't confirm that.

 

At least they didn't give the mice questionnaires afterwards to see if the swimming exercise produced improvements on self-reported fatigue scores.

 

how do they diagnose the mice given this difficulty with answering questions in the first place?

 

Ugh and utterly pointless.

I think they're engaged in Survival, Evasion, Resistance, and Escape training and someone confused marines and murines.