Nmda-Receptor Blockade Changed Micrornas Expression and Apoptotic Gene Levels in Dorsolateral Striatal Glioblastoma to Reduce Tumor Growth and Reverse Behavioral Impairments in Rats Publisher Pubmed



Davisaraei YB ; Nateghi S ; Delphi L ; Tirgar F ; Rostami F ; Sardari M ; Kouhkan F ; Rezayof A
Source: Neuroscience Published:2026

Abstract

The present study examined the involvement of the glutamatergic NMDA receptor (NMDAR) signaling pathway, specific microRNAs and apoptotic genes in the molecular and behavioral characteristics of glioblastoma multiforme (GBM) implanted into the dorsolateral striatum (DLS) in male Wistar rats. Following stereotaxic surgery, the C6 glioma cell line was implanted into the DLS to induce GBM (DLS-GBM), as confirmed by Magnetic Resonance Imaging (MRI) and Hematoxylin and Eosin (H&E) staining. Locomotor activity and exploratory behaviors were assessed using the Open Field test at 6 and 13 days post-induction of DLS-GBM, revealing alterations in these behaviors. Moreover, the DLS-GBM affected cognitive function, as animals underwent habituation followed by exposure to identical objects in the Novel Object Recognition test to assess memory performance. Repeated intra-DLS-GBM microinjections of the selective NMDAR antagonist D-AP5 (6 µg/rat) reduced the tumor volume and weight, increased survival rates, and improved behavioral outcomes. Additionally, the elevated levels of specific microRNAs (miRNAs) were associated with tumor progression, with D-AP5 lowering their expression compared to the untreated GBM group. Interestingly, D-AP5 treatment increased the expression of apoptotic genes, including Caspase-3 (9.2 folds), Caspase-9 (5.7 folds), Bax (3.5 folds), and Bak (2.7 folds), suggesting anti-tumoral effects of D-AP5 on glioblastoma cells. Taken together, these findings suggest that the blockade of NMDARs may offer therapeutic benefits by reducing tumor size and improving GBM-associated behavioral changes. Furthermore, the altered expression of specific miRNAs and apoptotic genes highlights their potential roles in GBM progression and regulatory pathways. © 2026 International Brain Research Organization (IBRO)