Cerebrolysin ameliorates ketamine-mediated anxiety and cognitive impairments via modulation of mitochondrial function and CREB/PGC-1a pathway

Mol Brain. 2025 Nov 7;18(1):84. doi: 10.1186/s13041-025-01255-1.

ABSTRACT

Schizophrenia is known as a complex and devastating mental disorder due to its profound impact on individuals, families, and society. Emerging evidence proposes that mitochondria play a central role in schizophrenia. Here, we investigated whether cerebrolysin (CBL) can alleviate anxiety-like behaviors and cognitive deficits through a mechanism involving the CREB/PGC-1α pathway. In this study, 30 male BALB/c mice were randomly assigned to three different groups: Control, Ketamine, and Ketamine + CBL. Intraperitoneal injection of ketamine was performed at 20 mg/kg for 14 consecutive days. CBL was delivered intraperitoneally at 2.5 mL/kg once daily for seven days, starting from the 8th day to the 14th day of the experiment. The novel object recognition and elevated plus-maze tests were used to assess episodic-like memory and anxiety, respectively. Hippocampal tissue was examined not only for alterations in mitochondrial activity, encompassing ATP production and levels of reactive oxygen species (ROS), but also for estimating CREB, p-CREB, and PGC-1α protein levels. Behavioral results indicated that treatment with CBL reversed anxiety-like behavior and cognitive dysfunction caused by ketamine. Additionally, ketamine increased the production of ROS and reduced ATP levels in the hippocampus, while CBL treatment restored these changes. Furthermore, CBL therapy upregulated the hippocampal expression of the proteins CREB, p-CREB, and PGC-1α compared with the ketamine-treated animals. It is speculated that treatment with CBL can attenuate ketamine-induced cognitive deficits and anxiety-like behaviors through the upregulation of the CREB/PGC-1α pathway and the improvement of mitochondrial function.

PMID:41204270 | DOI:10.1186/s13041-025-01255-1