Micro RNA 146a gene variant / TNF-α / IL-6 / IL-1 β; A cross-link axis inbetween oxidative stress, endothelial dysfunction and neuro-inflammation in acute ischemic stroke and chronic schizophrenic patients

Highlights

• CG and GG hsa-miR-146a genotypes were associated with increased risk of schizophrenia and AIS in schizophrenic patients.

• CG and GG hsa-miR-146a genotypes were significantly associated with thrombomodulin decrement levels and PANSS scores.

• Also, they were significantly associated with TNF-α, IL-6, IL-1 β, PAI-1, and 8-OHdG increment.

• Oxidative stress and DNA damage as a result of the neuro-inflammatory status originated from the hsa-miR-146a C>G gene SNP.

• This confirms their role in the pathogenesis of schizophrenia and its associated AIS risk.

Abstract

This work was purposed to speculate the possible association of rs2910164hsa-miR-146a C>G gene single nucleotide polymorphism in the pathogenesis of schizophrenia and subsequently their relevance to neuro-inflammatory, vascular and oxidative stress pathways as acute ischemic stroke (AIS) risk factors in chronic schizophrenic patients. 450 subjects, 150 healthy controls (group I), 150 chronic schizophrenic patients without any evidences of stroke (group II) and 150 chronic schizophrenic patients with AIS (group III) were included. Genotypes (CC, CG&GG) for hsa-mir-146a gene polymorphism were identified using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP technique. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1 β), plasminogen activator-inhibitor 1 (PAI-1), thrombomodulin (TM) and 8-Hydroxy-2-deoxyguanosine (8-OHdG) serum levels were immunoassayed. Complete lipid profile was estimated. The CG and GG hsa-miR-146a genotypes were associated with increased risk of both schizophrenia and AIS in schizophrenic patients with thrombomodulin levels decrement in group II& III. On the other side, the risk genotypes were associated significantly with positive and negative syndrome scale PANSS scores, TNF-α, IL-6, IL-1 β, PAI-1, and 8-OHdG increment levels in both groups II & III. By contrast, the CG and GG hsa-miR-146a genotypes did not affect the neuro-inflammatory and oxidative stress markers in healthy controls. These findings illustrate a new mechanism strengthening the occurrence of oxidative stress and DNA damage as a result of the neuro-inflammatory and endothelial dysfunction status originated from the hsa-miR-146a C>G gene single nucleotide polymorphism, thus, confirming their role in the pathogenesis of schizophrenia and its AIS risk.

Introduction

Schizophrenia is a chronic crushing mental disorder that is presented mainly by positive, negative and cognitive symptoms [1,2]. Its clinical course is usually characterized by recurrent relapses that cause an additional burden on cognitive performance, treatment response, and psychosocial functions [3]. The chronicity of schizophrenia and its drug-resistant course may also favor some neurodegenerative processes, although the proof of neuronal death in schizophrenia is highly controversial [4]. Chronic schizophrenic patients were approved to have two to three times' higher risk of premature death than general population, with life expectancy decrement of 15–20 years. Basically, acute ischemic stroke (AIS) includes brain blood flow obstruction with irreversible brain damage, is considered one of the main causative leading agents of schizophrenic patients premature death [5]. Despite the great controversy in schizophrenia pathogenesis and its role in AIS incidence, few studies have established an association between environmental-genetic deregulations, neuro-inflammation, thrombosis, oxidative stress and this illness [6]. The principal underlying cause of AIS is vascular thromboembolic occlusion [7]. Importantly, endothelial-generated anti- and pro-coagulant residues are un-equivalently distributed throughout the vascular bed. Endothelial cells exerts an anticoagulant activity by expressing tissue factor pathway inhibitor, like thrombomodulin (TM) which binds thrombin and promotes protein C and thrombin activated fibrinolysis inhibitor (TAFI) segmentation, thereby obstacles coagulation and inducing fibrinolysis [8]. Even though, endothelial cells also show a procoagulant activity, as it manufactures plasminogen activator inhibitor (PAI-1), the main physiological inhibitor of tissue plasminogen activator (tPA) [9]. PAI-1 causes inactivation of urokinase plasminogen activator (uPA) that regulates the production of plasmin [10]. In addition, increased levels of PAI-1 have been recognized as a hallmark of endothelial dysfunction [11]. Bleeding or hypercoagulability and thrombosis may occur as a result of acquired alterations in the dynamic balance in vascular pathophysiology [12]. MicroRNAs (miRNAs) are one of the main eukaryotic genetic modulators that have been approved to be responsible for regulation of many cellular pathways. Alteration in circulating miRNAs levels has been documented to be intimately associated with incidence of many different human diseases, such as type 2 diabetes, cerebral stroke, neuropsychiatric disorders and immunological diseases [[13], [14], [15]]. Recently, hsa-miR-146a was identified as a potential diagnostic biomarker in various diseases with its gene located on the long arm of chromosome 5 (5q 33.3) with about 109 bases length (via NCBI) [16]. Cytokines are immune/inflammatory protein modulators that act as chemical messengers between immune cells modify the neurotransmitters and neuro-endocrine hormones metabolism, thus affecting neural development and behavioral changes [17]. Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α are a group of proinflammatory cytokines which have been indulged as a cardinal axis of a common pathway of AIS incidence and schizophrenia liability factors. Its production and signaling are intimately regulated by a various genes that may be accused for schizophrenia [18]. Oxidative stress has hazardous damaging effects on different cellular components and causes DNA damage with subsequent formation of 8-hydroxy-2' -deoxyguanosine (8-OHdG) that has been largely used as a biomarker for oxidative stress DNA damage [19]. This study was undertaken to investigate the possible contribution of rs2910164 hsa-miR-146a C>G gene single nucleotide polymorphism to the molecular pathogenesis of schizophrenia and highlights their relation with neuro-inflammatory, endothelial dysfunction and oxidative stress pathways as AIS risk factors in patients with chronic schizophrenia.