Supraphysiological
oxygen concentrations are toxic to the developing brain. Inflammatory processes increase the risk for
brain injury.
Sigma-1 receptor agonists are potent suppressors of
inflammation-related events and are powerful immunomodulatory and antioxidative agents.
Neuroprotective effects of
sigma-1 receptor agonists have been described previously for neonatal and adult models of
brain injury. The aim of this study was to assess the selective
sigma-1 receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE-084) in models of
inflammation-sensitized
hyperoxia-induced developing
brain injury. For in vivo studies, rat pups were randomly presensitized with 1)
lipopolysaccharide or 2) vehicle on postnatal day 3. On day 6, pups received either 1)
PRE-084 or 2) vehicle and were subsequently exposed to hyperoxic conditions for 6, 12, or 24 hr. At the end of exposure, animals were sacrificed and brains were processed for
caspase-3 analysis using immunohistochemistry and Western blotting. For in vitro studies, oligodendroglial cells were subjected to hyperoxic conditions in the presence or absence of proinflammatory
cytokines and
PRE-084. Cell membrane integrity and cell viability were assessed by means of
lactate dehydrogenase and 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays. Inflammatory presensitization significantly increased
hyperoxia-induced injury both in vivo and in vitro.
PRE-084 administration did not attenuate damage. Sigma-1 receptor agonists have been described as a promising therapeutic strategy for
brain injury. We were not able to confirm this in the present model. The exact mechanisms of action of sigma-1 receptor agonists as well as the pathophysiologic pathways involved in
hyperoxia-induced injury in the developing brain remain to be elucidated.