The role of neuroinflammatory markers in a preeclamptic rat model.

Abstract

Introduction: Preeclampsia (PE) is a clinical complication of pregnancy characterised with the new onset of hypertension and proteinuria, and/or organ dysfunction. Globally, it is associated with maternal and perinatal morbidity and is a major cause for concern. If undiagnosed, preeclampsia can lead to eclampsia, which is characterised by an onset of seizures (convulsions). Thus, neurological consequences have been reported in both PE mothers and their offspring. Materials and Methods: This study investigated the role of neuroinflammation and oxidative stress in the brain of an Nꭃ-nitro-L-arginine methyl (L-NAME) induced Preeclamptic rat model through birth to late postnatal days in the mother and the offspring. Pregnant rats were divided into control, early onset and late onset PE groups. Blood pressure, urine volume and proteinuria were measured on gestational day (GD) 0, 12 and 17 to establish PE. At GD 19, postnatal day (PND) 1 and 60, rats and their pups were sacrificed and brain excised. Prior to sacrifice at PND 60, the offspring were subjected to neurobehavioural studies to test for memory performance and locomotor activity. Ionized calcium binding adaptor molecule 1 (IBA1) and Excitatory amino acid transporter 1 (EAAT1), and oligodendrocyte transcription factor 2 (OLIG2) expression in the cortex and cerebellum were analysed by immunohistochemistry. Additionally, cortical and cerebellar tissues were homogenised for further biochemical analysis of oxidative stress such as Nitric oxide (NO), lipid peroxidase superoxide dismutase (SOD), glutathione (GSH), lipid peroxidase (LPO) and purinergic enzyme activities at PND 60. Results: We found an increase in blood pressure accompanied by proteinuria and a low foetal count in the L-NAME treated groups. Neuroinflammation was evident in the treated group at birth and PND 60 as shown by an increase in the number of IBA1 expressing activated microglia with a simultaneous reduction in the immunoexpression of EAAT1. PE- induced axonal damage was noted as shown by a reduced number of oligodendrocytes. At PND 60, PE groups show alteration in oxidative stress markers, increased acetylcholinesterase activity, and decreased purinergic enzymes activities such as adenosine triphosphatase (ATPase) and ecto-nucleoside triphosphate diphosphohydrolase (ENTPDase). The offspring at PND 60 also display reduced memory performance and locomotor activity, which was accompanied by an increased number of activated microglia, down-regulated the immunoexpression of EAAT1 and reduced number of oligodendrocyte cells.

Discussion and conclusion: This study demonstrates neuroinflammation and axonal damage in PE at delivery which also persists into later life. This finding might be attributed to systemic inflammation and vulnerability of blood-brain barrier associated with PE which can cause crossing over of substances from the systemic environment thereby causing insult to the brain. Alteration in oxidative stress markers and an increase in acetylcholinesterase in the brain usually pinpoint to neurovascular/ neurodegenerative disease, this might be an indication of PE been predisposing to neurodegenerative disease later in life. We, therefore, conclude that a history of PE predisposes mothers and their offspring to a higher risk of neurological complications later in life.