The Anti-inflammatory Compound Candesartan Cilexetil Improves Neurological Outcomes in a Mouse Model of Neonatal Hypoxia

Abstract

Recent studies suggest that mild hypoxia-induced neonatal seizures can trigger an acute neuroinflammatory response leading to long-lasting changes in brain excitability along with associated cognitive and behavioral deficits. The cellular elements and signaling pathways underlying neuroinflammation in this setting remain incompletely understood but could yield novel therapeutic targets. Here we show that brief global hypoxia-induced neonatal seizures in mice result in transient cytokine production, a selective expansion of microglia and long-lasting changes to the neuronal structure of pyramidal neurons in the hippocampus. Treatment of neonatal mice after hypoxia-seizures with the novel anti-inflammatory compound candesartan cilexetil suppressed acute seizure-damage and mitigated later-life aggravated seizure responses and hippocampus-dependent learning deficits. Together, these findings improve our understanding of the effects of neonatal seizures and identify potentially novel treatments to protect against short and long-lasting harmful effects.

Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models

“…This data showed that TLR2 plays a role in initiating inflammation after perinatal brain injury [ 85 , 86 ]. Supporting this data, the use of Candesartan Cilexetil, a drug which reduces levels of TLR2, has been shown to improve neuronal damage after hypoxia in mice, and also improve the long-lasting neurological outcomes [ 11 ]. Importantly, the response of TLR2 to sterile (e.g., HI) or non-sterile inflammation (e.g., LPS to mimic bacterial infection) differs on the pre-clinical model [ 84 ].…”

“…The role of inflammation in neonatal seizures is not fully understood. We know that targeting inflammation before hypoxia reduced the number of seizure events and the duration of seizures [ 10 , 11 ]. The mechanism by which this targeting of inflammation reduces seizure activity will require further investigation.…”

“…In recent years, inflammation has been implicated in neonatal brain damage following perinatal stress. Induction and activation of microglia and astrocytes are hallmarks of neuroinflammation, which occurs in response to hypoxia and hypoxic ischemia in neonates [ 11 , 70 ]. Studies have shown that exposure of the neonatal brain to hypoxia, thereby causing an inflammatory response, is associated with long-lasting changes to neuronal morphology within the hippocampus and other vulnerable structures of the brain [ 71 ].…”

“…Circulating cytokines and neuroimmune cells such as microglia are the targets of several studies that are investigating the potential use of these components as biomarkers for neonatal brain injury. Additionally, targeting inflammation improves acute and long-lasting effects after hypoxia and hypoxic ischemia in mice [ 11 , 70 ].…”

Neonatal Seizures and Purinergic Signalling

“…Purinergic signalling is involved in many processes known to contribute to epileptogenesis and to potentiate damage. Targeting inflammation following neonatal seizures, a process in which purinergic signalling is heavily involved, has shown promise to reduce the development of epilepsy and behavioural deficits [302].…”