article · Biomedicine & Pharmacotherapy
Cisplatin is a widely used cancer chemotherapy, but it frequently leads to cognitive impairment, commonly termed chemo-brain. This preclinical investigation evaluated whether vildagliptin, a DPP-4 inhibitor, could protect against cisplatin-induced neurotoxicity in rats. Daily oral administration of vildagliptin across four weeks reversed cognitive deficits in behavioural assessments, including the Morris water maze and Y-maze. The treatment also reduced structural neurodegeneration, curtailed amyloid plaque deposits, and improved cholinergic neurotransmission by downregulating acetylcholinesterase. Biochemical analyses demonstrated that vildagliptin suppressed oxidative stress, inhibited neuroinflammation, and prevented hippocampal neuronal apoptosis. Furthermore, it promoted cell survival and neurogenesis through the upregulation of BDNF and PCNA, actions driven predominantly by activating AMPK, Akt, and CREB signalling pathways. These findings demonstrate that vildagliptin mitigates neurotoxic damage associated with cisplatin treatment in an animal model.
Cognitive deficits caused by cisplatin chemotherapy significantly undermine the quality of life for cancer patients. Demonstrating that an existing therapeutic agent can counteract neurodegeneration, neuroinflammation, and memory impairment in animal models offers a valuable biological foundation for developing supportive treatments that preserve brain health during cancer therapies.
This research suggests a potential drug repurposing pathway for vildagliptin as a supportive therapy to prevent chemotherapy-related cognitive decline in oncology patients. Pharmaceutical developers and clinical researchers focusing on supportive cancer care represent the primary audience. Because the findings are based entirely on an in vivo rodent study, the technology remains at an early preclinical stage and requires clinical trials to evaluate human safety and therapeutic efficacy.
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Cisplatin (CP) is a broad-spectrum antineoplastic agent used to treat many human cancers. Nonetheless, most patients receiving CP suffer from cognitive deficits, a phenomenon termed "chemo-brain". Recently, vildagliptin (Vilda), a DPP-4 inhibitor, has demonstrated promising neuroprotective properties against various neurological diseases. Therefore, the present study aims to investigate the potential neuroprotective properties of Vilda against CP-induced neurotoxicity and elucidate the underlying molecular mechanisms. Chemo-brain was induced in Sprague-Dawley rats by i.p injection of CP at a dose of 5 mg/kg once weekly for four weeks. Vilda was administered daily at a dose (10 mg/kg; P.O) for four weeks. The results revealed that Vilda restored the cognitive function impaired by CP, as assessed by the Morris water maze, Y-maze, and passive avoidance tests. Moreover, Vilda alleviated the CP-induced neurodegeneration, as shown by toluidine blue staining, besides markedly reduced amyloid plaque deposition, as evidenced by Congo red staining. Notably, Vilda boosted cholinergic neurotransmission through the downregulation of the acetylcholinesterase enzyme. In addition, the neuroprotective mechanisms of Vilda include diminishing oxidative stress by reducing MDA levels while raising GSH levels and SOD activity, repressing neuronal apoptosis as shown by elevated Bcl-2 levels together with diminished Bax and caspase-3 expressions, inhibiting neuroinflammation as shown by decreased GFAP expression, and finally boosting hippocampal neurogenesis and survival by upregulating expressions of BDNF and PCNA. These effects were mainly mediated by activating AMPK/Akt/CREB signaling cascades. In summary, Vilda can be considered a promising candidate for guarding against CP-induced chemo-brain and neurodegeneration, thus improving the quality of life of cancer patients.
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DOI: 10.1016/j.biopha.2023.114238
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