The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and multiple sclerosis

Abstract

Sleep and circadian abnormalities are prevalent and burdensome manifestations of diverse neuro-immune diseases, and may aggravate the course of several neuropsychiatric disorders. The underlying pathophysiology of sleep abnormalities across neuropsychiatric disorders remains unclear, and may involve the inter-play of several clinical variables and mechanistic pathways. In this review, we propose a heuristic framework in which reciprocal interactions of immune, oxidative and nitrosative stress, and mitochondrial pathways may drive sleep abnormalities across potentially neuroprogressive disorders. Specifically, it is proposed that systemic inflammation may activate microglial cells and astrocytes in brain regions involved in sleep and circadian regulation. Activated glial cells may secrete pro-inflammatory cytokines (for example, interleukin-1 beta and tumour necrosis factor alpha), nitric oxide and gliotransmitters, which may influence the expression of key circadian regulators (e.g., the Circadian Locomotor Output Cycles Kaput (CLOCK) gene). Furthermore, sleep disruption may further aggravate oxidative and nitrosative, peripheral immune activation, and (neuro) inflammation across these disorders in a vicious pathophysiological loop. This review will focus on chronic fatigue syndrome, bipolar disorder, and multiple sclerosis as exemplars of neuro-immune disorders. We conclude that novel therapeutic targets exploring immune and oxidative & nitrosative pathways (p.e. melatonin and molecular hydrogen) hold promise in alleviating sleep and circadian dysfunction in these disorders.

Neuroinflammation in Bipolar Depression

“…Many immune cells types show daily fluctuations in human and rodents' blood. On the other hand, both circadian rhythms and sleep plays a regulatory role on immune system: sleep is involved into the maintenance of Th1 and Th2 homeostasis, the activity of effector and regulatory t cells, and natural killer (NK) cells (90). Sleep seems also to be involved in the transcription regulation of pro and antiinflammatory factors (91).…”

On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

“…Also, OS has been implicated in poor sleep and circadian abnormalities in MS . Evidence suggests that ROS in neurons play an essential role in the regulation of sleep.…”

“…Sleep disturbance plays a critical role in the development neurodegeneration 161 and poor sleep is common in patients with MS. 162,163 Importantly, MtD is strongly associated with sleep disorders. 164,165 Also, OS has been implicated in poor sleep and circadian abnormalities in MS. 166 Evidence suggests that ROS in neurons play an essential role in the regulation of sleep. Indeed, it has been hypothesized that a key function of sleep is to attenuate the damaging effects of OS by acting as an antioxidant, 167,168 suggesting that impaired sleep in MS promotes increased OS and the progression of the disease.…”

Insomnia and other sleep complaints in inflammatory versus noninflammatory skin disorders: An observational case‐control study

“…The activated glial cells will produce pro‐inflammatory cytokines such as IL‐1β (interleukin 1‐beta) and TNF‐α (tumor necrosis factor‐alpha). These cytokines, as well as nitric oxide and gliotransmitters, will affect sleep . In turn sleep deprivation aggravates the immune system and causes stress and more inflammation, which leads to a vicious cycle of aggravating the disease as shown in patients with fibromyalgia in Milrad's study …”