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

Andy

Andy

Retired committee member
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
 
Kitty said:
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.
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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.
 
Ugh and utterly pointless.

Animals were maintained on a 12-hour light-dark cycle with ad-libitum access to good quality standard chow diet and RO water. Before initiating the experiments, animals were acclimatized to the prevailing laboratory conditions to nullify the effect of environmental stress. All animal experimentation was carried out between 9:00 to 17:00.
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FST was selected to emulate the phenotypical and pathological changes associated with CFS as the validity of this model for stress-induced anxiety and depression has been regarded as the highest after mice were exposed to chronic forced swimming. The immobility time of FST has been used for a long time now as a validated experimental model for testing antidepressant activity [20]. The procedure is thus repurposed to mimic a state of chronic fatigue in mice when it is forced to swim daily inside a glass jar with a rectangular shape of dimensions 25 × 12 × 25 cm 3 filled up to 15 cm with clean, fresh water maintained at 23–25 °C [21]. This protocol is designed such that for a period of 15 days, mice were made to swim for a total session of 6 min where the immobility time was noted using a stopwatch. Mouse that does not drown and is said to be immobile following cessation of any kind of struggling movement or when it appears to be floating passively over the surface (Porsolt’s Forced swim test), only making necessary movements to facilitate breathing and staying afloat [21–24]. The immobility time was recorded for alternate days for 15 days while FST was performed daily.
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I think they're engaged in Survival, Evasion, Resistance, and Escape training and someone confused marines and murines.
 
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