Inhibition of phosphodiesterase-4 mitigates stress-re-stress-paradigm induced mitochondrial perturbations in rats exhibiting PTSD-like symptoms

被引：0
作者：
Prajapati S.K. [1 ,2 ]
Chippala R. [1 ]
Krishnamurthy S. [1 ]
机构：
[1] Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi
[2] Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, 33613, FL
来源：
Neuroscience and Behavioral Physiology | 2023年 / 53卷 / 8期
关键词：
cAMP; Hypothalamic-pituitary-adrenal-axis; Mitochondrial bioenergetics; Phosphodiesterase-4; inhibitor; Post-traumatic stress disorder; Stress re-stress;
D O I：
10.1007/s11055-023-01505-6
中图分类号：
学科分类号：
摘要：
Mitochondria are involved in the pathogenesis of post-traumatic stress disorder (PTSD). Phosphodiesterase-4 (PDE-4) regulates mitochondrial-dependent intracellular cAMP levels in neuropsychiatric disorders. Inhibition of PDE-4 with rolipram (RPM) has anxiolytic and psycho-mimetic properties. However, the role of PDE-4 inhibitor in PTSD remains unclear. Therefore, it may be useful in the treatment of comorbidities that resemble PTSD. The effects of RPM (PDE-4 inhibitor) and paroxetine (PAX) on mitochondrial dysfunction in the amygdala were investigated using the stress re-stress (SRS) model of PTSD. On day 2 (D-2), male rats were exposed to foot shock at intensity 2 mA for 10-second followed by halothane anesthesia. The rats were then subjected to re-stress of foot shock on D-8 to D-32 at 6-day intervals. RPM (0.5, 1, and 2 mg/kg) and PAX (10 mg/kg) treatments given orally from D-8 to D-32. RPM (1 and 2mg/kg) significantly attenuated SRS-induced PTSD-like symptoms like fear response, anxiety-like behavior, cognitive deficits and hypocorticosteronism. The SRS-induced decrease in mitochondrial respiratory complex (I, II, IV, and V) activity, respiratory control rate (RCR) and cAMP level in the amygdala were ameliorated by RPM. Further, sub-chronic treatment with RPM reduced the SRS-induced rise in ADP/ATP ratio in the amygdala. RPM ameliorated the SRS-induced alteration in mitochondrial membrane potential (MMP) and cytochrome-c levels in the amygdala. Thus, findings suggested that cAMP-dependent regulation of ADP/ATP ratio and mitochondrial function could be a potential mechanism for the anti-PTSD-like effect of RPM in the SRS model. © 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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页码：1330 / 1346
页数：16
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