Inhibiting inflammation in a model of transient focal cerebral ischemia. Short- and long-term effects

  1. FERNANDEZ UGIDOS, IRENE
Supervised by:
  1. Arsenio Fernández López Director
  2. Diego Pérez Rodríguez Director

Defence university: Universidad de León

Fecha de defensa: 15 November 2019

Committee:
  1. Rebeca Diez Alarcia Chair
  2. Amy Victoria Poole Secretary
  3. Jenny Fraser Committee member
Department:
  1. BIOLOGÍA MOLECULAR

Type: Thesis

Teseo: 612595 DIALNET

Abstract

Cerebrovascular accident or stroke is one of the leading causes of mortality, the first cause of permanent disability and the second cause of dementia in developed countries. The lack of effective treatments requires an urgent search for new therapies against this pathology. In this regard, this study aims to gain insight into the mechanisms underlying the transient focal ischemia model related to the response to inflammation. The first chapter of this study focuses on the effect of a novel anti-inflammatory agent, 2-hydroxyarachidonic acid (2OAA) after 24 h of reperfusion. A single dose of 2OAA reduces the infarct volume, the transcription and activity of phospholipase A2, and the lipid peroxidation in the ischemic hemisphere. The decrease in transcriptional activity of anti-oxidant enzymes suggests that the neuroprotective effect of 2OAA relies on preventing oxidative stress rather than promoting anti-oxidant responses. This agent seemed promising in short-term studies, but its weak stability makes it inappropriate for long-term studies. The second and third chapters analyze the effects of the non-steroidal anti- inflammatory agent meloxicam. The second chapter focuses on the neuroprotective effect of meloxicam after 48 h reperfusion measuring both infarct volume and neurological deficit. Neuroprotection obtained with 1 mg/kg of meloxicam was maintained for seven days after reperfusion. Moreover, the chronic but not the acute dose of meloxicam improved the motor deficit. This behavioral improvement encompassed an increase in axonal sprouting after seven days in the damaged area, highlighting the potential of this agent to provide long-term recovery. The third chapter addresses the analysis of both acute and chronic administration of meloxicam on the glial scar after seven days of reperfusion. Glial scars in both the cerebral cortex and striatum were studied as well as the newly migrating neurons. Meloxicam reduced astrocyte activation after stroke in the cerebral cortex but not in the striatum after both acute and chronic treatments, suggesting an early modulation of the glial scar confined to the first 48 hours after reperfusion. This work provides a different view on the use of some anti-inflammatory agents with preferential selectivity for cyclooxygenase-2 and some remaining activity on cyclooxygenase-1 inhibition. The proper control of their dosage could provide effective treatments for the pathology of stroke.