ABSTRACT
Post-traumatic stress disorder (PTSD) is a chronic incapacitating condition with recurrent experience of trauma-related memories, negative mood, altered cognition, and hypervigilance. Agglomeration of preclinical and clinical evidence in recent years specified that alterations in neural networks favor certain characteristics of PTSD. Besides the disruption of hypothalamus-pituitary-axis (HPA) axis, intensified immune status with elevated pro-inflammatory cytokines and arachidonic metabolites of COX-2 such as PGE2 creates a putative scenario in worsening the neurobehavioral facet of PTSD. This review aims to link the Diagnostic and Statistical Manual of mental disorders (DSM-V) symptomology to major neural mechanisms that are supposed to underpin the transition from acute stress reactions to the development of PTSD. Also, to demonstrate how these intertwined processes can be applied to probable early intervention strategies followed by a description of the evidence supporting the proposed mechanisms. Hence in this review, several neural network mechanisms were postulated concerning the HPA axis, COX-2, PGE2, NLRP3, and sirtuins to unravel possible complex neuroinflammatory mechanisms that are obscured in PTSD condition.
Subject(s)
Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/diagnosis , Stress Disorders, Post-Traumatic/metabolism , Hypothalamo-Hypophyseal System/metabolism , Cyclooxygenase 2 , Dinoprostone/metabolism , Pituitary-Adrenal System/metabolismABSTRACT
NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.
Subject(s)
Antioxidants , Enzyme Inhibitors , Illness Behavior , Oxidative Stress , Resveratrol , Sirtuins , Animals , Antioxidants/pharmacology , Enzyme Inhibitors/pharmacology , Fluoxetine/pharmacology , Illness Behavior/drug effects , Illness Behavior/physiology , Lipopolysaccharides , Male , Mice , Oxidative Stress/drug effects , Resveratrol/pharmacology , Sirtuins/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Recent research emphasizes the central role of neuroinflammation in complex neurological disorders such as Alzheimer's disease, Parkinson's disease, depression, multiple sclerosis, and traumatic brain injury. Multiple pathological variables with identical molecular mechanisms have been implicated in the development of CNS inflammatory diseases. Therefore, one of the most crucial tasks in the management of CNS disorders is the alleviation of neuroinflammation. However, there are many drawbacks of new pharmacological drugs used in the management of CNS disorders, including medication side effects, and treatment complications. There is a growing inclination towards bioactive constituents of natural origin to unearth the potential remedies. Cordycepin, an adenosine analogue, is one such bioactive constituent with multiple actions, viz., anticancer, anti-inflammatory, hepato-protective, antidepressant, anti-Alzheimer's, anti-Parkinsonian and immunomodulatory effects, along with the promotion of remyelination. This review highlights the converging neuroinflammatory targets of cordycepin in Alzheimer's disease, Parkinson's disease, and depression, to substantiate its anti-neuroinflammatory property. Cordycepin acts by downregulation of adenosine A2 receptor, inhibition of microglial activation, and subsequent inhibition of several neuroinflammatory markers (NF-κB, NLRP3 inflammasome, IL-1ß, iNOS, COX-2, TNF-α, and HMGB1). Cordycepin mitigates LPS-mediated toll-like receptor activation by activating adenosine receptor A1, thereby improving antioxidant enzymes (superoxide dismutase, glutathione peroxidase) levels. These pieces of evidence point to the probable anti-neuroinflammatory mechanisms of cordycepin, which could facilitate the development of new remedies against neuroinflammation-associated CNS disorders.
