Myrtenol modulates TWEAK/TLR4-NF-κB, miR-21, PTEN, and ERK-1 expressions and improves behavioral outcomes in a rat glioblastoma model.

Glioblastoma (GBM) triggers profound neuroinflammatory and oncogenic signaling that contributes to both tumor progression and behavioral disturbances. Myrtenol (MYRT), a naturally occurring monoterpene, exhibits anti-inflammatory and neuroprotective properties, but its effects on GBM-related molecular pathways remain poorly defined. This study investigated the impact of MYRT on key inflammatory and oncogenic mediators, including TWEAK, NF-κB, miR-21, PTEN, ERK-1, TLR4, and cytokine balance, alongside behavioral outcomes, in a rat model of GBM. Male Wistar rats were assigned to sham, vehicle, or MYRT (25, 50, and 100 mg/kg) groups. Behavioral alterations were assessed using the open field test (OFT). GBM induction was confirmed histopathologically using Cresyl Violet (Nissl) staining. Additionally, hematoxylin and eosin (H&E) staining was performed to examine histopathological changes in the brain tissues of the treatment groups. Gene expression of TWEAK, NF-κB, miR-21, PTEN, and ERK-1 was quantified by real-time PCR. Protein expression of TLR4 and NF-κB and the cerebral IL-1β/IL-10 ratio were assessed to evaluate neuroinflammatory status. GBM induction significantly increased anxiety-like behavior, evidenced by reduced center time, increased grooming, and decreased rearing in the OFT. These behavioral abnormalities were accompanied by marked histopathological disruption, upregulation of TWEAK, NF-κB, miR-21, ERK-1, TLR4, and NF-κB expressions, an elevated IL-1β/IL-10 ratio, and suppression of PTEN. MYRT treatment, particularly at 100 mg/kg, was associated with significant improvements in behavioral deficits, reduction of tumor burden and mitotic figures, lower levels of inflammatory and oncogenic signaling markers, and higher PTEN expression and a more balanced cytokine profile. Lower MYRT doses showed partial effects. For miR-21, a nonsignificant numerical reduction was observed at the highest MYRT dose. MYRT treatment correlates with reduced GBM-induced behavioral, inflammatory, and molecular disturbances. These observations are consistent with the modulation of interconnected inflammatory and oncogenic pathways, including TWEAK, TLR4/NF-κB, PTEN, and ERK-1, as well as with a shift towards cytokine homeostasis. The nonsignificant numerical trend in miR-21 expression warrants further investigation.