The Effect of Two Novel Anti-Inflammatory Drugs on Sensorimotor Gating and Microglial Activation in the Poly I:C Rodent Model of Schizophrenia

• Main Authors: Shelton, Heath W, Gill, W. Drew, Gabbita, Prasad, Brown, Russell W
• Format: Others
• Published: Digital Commons @ East Tennessee State University 2019
• Subjects: Schizophrenia; Neuroinflammation; TNF-alpha; Microglia; Poly I:C; Behavioral Problems or Disorders; Inflammation
• Online Access: https://dc.etsu.edu/asrf/2019/schedule/160; https://dc.etsu.edu/cgi/viewcontent.cgi?article=1273&context=asrf

Antipsychotic medications remain the first line of treatment for individuals diagnosed with schizophrenia (SCZ). However, antipsychotic treatment is often not compliant due to dysregulation of both the central (CNS) and autonomic (ANS) nervous systems, resulting in debilitating dose-dependent side effects. Recent work suggests a new approach for treatment of SCZ that could potentially lower treatment doses and reduce side effects. Increased neuroinflammation has been shown in patients diagnosed with SCZ, particularly within the prefrontal cortex (PFC) and hippocampal (HPC) regions of the brain. Tumor necrosis factor-alpha (TNFa) is one of the key pro-inflammatory cytokines observed to be secreted during the inflammatory response. When TNFa is chronically secreted, resident CNS microglia become pro-inflammatory and toxic to the local environment. Microglial activation alongside of dopamine dysregulation thereby results in both the behavioral and neuroinflammatory aspects of SCZ. In this study, we hypothesized dietary administration of two different novel TNFamodulators (PD2024 – Experiment 1 and PD340 – Experiment 2) developed by our collaborators from P2D Bioscience, Inc. (Cincinnati, OH) would alleviate auditory sensorimotor gating deficits and reduce microglial cell activation caused by neonatal polyinosinic:polycytidylic acid (Poly I:C) treatment in rats, which is a validated rodent model of SCZ. Four groups (Experiment 1: Poly IC/PD2024, Poly IC/Control, Saline/PD2024, Saline/Control and Experiment 2: Poly IC/PD340, Poly IC/Control, Saline/PD340, Saline/Control) were intraperitoneally administered either Poly I:C (2 mg/kg) or saline (0.9% NaCl) from postnatal days 5-7. From P30-67, animals were placed on the experimental diet containing either low (10 mg/kg) or high (30 mg/kg) doses of either PD2024 or PD340, whereas the control animals remained on a normal diet. Prepulse inhibition (PPI) was used to test for auditory sensorimotor gating (behavioral abnormalities) in both adolescence (P44-46) and in adulthood (P60-66). At P67, immunohistochemistry (IHC) and confocal microscopy were used to evaluate and examine microglial cell activation using the Iba1-GFP antibody (neuroinflammatory abnormalities) in the PFC and HPC. Results revealed auditory sensorimotor gating deficits in Poly IC/Controls were alleviated in both adolescence and adulthood with either PD2024 or PD340. It was also found that both TNFa modulators significantly reduced microglial activation in the HPC, but not the PFC. The data supports our hypothesis that dietary administration of PD2024 or PD340 alleviates behavioral deficits and decreases neuroinflammation generated from the Poly I:C rodent model of SCZ. Therefore, an approach with a TNFa modulator alongside of current antipsychotic medications could treat both the behavioral and neuroinflammatory aspects of SCZ.