Pathophysiological role of monoamine oxidase-A in the activation of indoleamine-2, 3-dioxygenase and neurodegeneration in the hippocampus induced by chronic intermittent hypoxia in rodents

Abstract

Obstructive sleep apnea (OSA) has been shown to be associated with major depressive disorder (MDD) in patients. However, there is a lack of pathophysiological mechanisms to depict the causal relationship. The hippocampus is an important brain region that manifests neuropathies in psychiatric disorders. Overactivation of monoamine oxidase-A (MAO-A) and cytokine-sensitive indoleamine-2,3-dioxygenase (IDO-1) have been reported in the brains of clinically depressed patients and animals, and leads to deregulated serotonin metabolism and neurodegeneration. Yet, the involvement of MAO-A and IDO-1 mediating hippocampal serotonin depletion and neurodegeneration resulting in depressive-like behavior in experimental animals under chronic intermittent hypoxia (CIH), a hallmark clinical manifestation of OSA patients, is largely unknown. In my study, I found that rats given CIH treatment (Apnea-Hyponea Index =60) displayed significant depressive-like behaviors. There were significant increases in the MAO-A activity, serotonin metabolic turnover, oxidative stress, nuclear factor kappa B (NFKB) cascade activation, neuroinflammation, IDO-1 activation and apoptotic markers in the hippocampus of CIH-treated rats. In addition, there were marked alterations in the neuroarchitecture of the CA1 and CA3 pyramidal neurons revealed by Golgi staining. Patients suffered from Cushing syndrome (CS) were shown to be co-morbid with sleep apnea reported in medical literature. Patients with CS are at a high risk of developing depression. However, the exacerbative effect of OSA on the progression of depressive-like behaviors in patients with CS is not clearly understood. Therefore, in the next study, rats were given repeated corticosterone (CORT) injections for 14 days and CIH treatment at day 8 lasting for a week. I found that CIH aggravated CORT-induced depressive-like behaviors in the rats through exacerbating the MAO-A activity resulting in oxidative stress, inflammation, and IDO-1 activation, leading to serotonin deficiency and neurodegeneration. The brain permeable multifunctional drug M30 possesses brain selective MAO-inhibition and iron-chelating antioxidative properties. Protective effects of M30 have been shown in animal and cell models of neurodegenerative diseases with its anti-oxidative, anti-inflammatory and anti-apoptotic effects. However, the beneficial effects of M30 against depression induced by CIH or by concurrent treatment of CIH and CORT remain elusive. In my studies, I found that M30 pre-treatment remarkably prevented the onset of depression, ameliorated serotonin turnover, oxidative stress, inflammation, IDO-1 activation, restored serotonin depletion and abrogated the impairment of dendritic abnormalities in the hippocampus induced by CIH and co-treatment of CIH and CORT. Obesity is a risk factor of OSA and the exacerbative effect of CIH on the hippocampal neurodegeneration and altered serotonin metabolism in obese mice is examined in the last study. C57Bl/6 mice were given high fat diet treatment (45% energy from fat) for 12 weeks and CIH treatment at 9th week lasting for a month. I found that elevated levels of MAO-A activity, oxidative stress, inflammation, IDO-1 activation, serotonin metabolic turnover and hippocampal neurodegeneration were the most prominent in high fat diet and CIH co-treated mice. Collectively, these findings suggest that the axis of MAO-A/Oxidative Stress/Inflammation/IDO-1/Neurodegeneration plays an important role in the induction of depressive-like behaviors under CIH conditions and co-morbid complications.