Abstract
Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA) receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC) staining, neuronal damage was assessed by Haematoxylin Eosin (H&E) staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP) was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.
Highlights
Stroke represents the leading cause of death and permanent disability for old people
We demonstrated that neither maslinic acid nor MK-801 was neuroprotective at a subthreshold dosage
These results indicated that the combination therapy of maslinic acid and MK-801 may be
Summary
Stroke represents the leading cause of death and permanent disability for old people. Several key factors have been implicated in ischemic cell death, including excitotoxicity, oxidative and nitrosative stress, and inflammation [3]. Excessive release of glutamate and N-methyl-D-aspartate (NMDA) receptor-related excitotoxicity has been regarded as major causes of brain tissue damage [1]. Molecules 2016, 21, 1093; doi:10.3390/molecules21081093 www.mdpi.com/journal/molecules increasing. Another the wayintake is to [4,5]. Attenuate the activation of the NMDA receptorofwith via blockingthe itsintake release[4,5]. Another way is to attenuate the activation the antagonists
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