Cerebral edema is a leading cause of mortality in
stroke patients. The purpose of this study was to assess a non-selective
opioid receptor agonist,
biphalin, in decreasing reducing
brain edema formation using both in vitro and in vivo models of
stroke. For the in situ model of
ischemia, hippocampal slices were exposed to
oxygen glucose deprivation (OGD) conditions and we observed that hippocampal water content was increased, compared to normoxia. Treatment with the mu agonist, Tyr-D-Ala', N-CH, -Phe4, Glyol-
Enkephalin (
DAMGO), delta
opioid agonists, D-pen(2), D-phe(5)
enkephalin (
DPDPE), and kappa agonist, U50 488, all significantly decreased brain slice water gain. Interestingly, the non-selective agonist,
biphalin, exhibited a statistically significant (P<0.01) greater effect in decreasing water content in OGD-exposed hippocampal slices, compared with mu, delta, and kappa selective
opioid agonists. Moreover,
biphalin exhibited anti-edematous effects in a dose responsive manner. The non-selective
opioid antagonist,
naloxone, returned the water content nearly back to original OGD values for all
opioid agonist treatments, supporting that these effects were mediated by an
opioid receptor pathway. Furthermore,
biphalin significantly decreased
edema (53%) and
infarct (48%) ratios, and neuronal recovery from
stroke, compared with the vehicle-treated groups in a 12h permanent
middle cerebral artery occlusion (MCAO) model of focal
ischemia.
Biphalin also significantly decreased the cell volume increase in primary neuronal cells exposed to OGD condition. These data suggest that
opioid receptor activation may provide neuroprotection during
stroke and further investigations are needed in the development of novel
opioid agonist as efficacious treatments for
brain ischemia.