Behavioural brain research · 2026
Pharmacological evidence suggesting the involvement of autophagy-related signaling in the cognitive effects of neuropeptide Y in an amyloid-β-induced model of Alzheimer's disease.
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Razi Pezhman, Rashtiani Samira, Rostampour Mohammad, Rohampour Kambiz, Jafari Adele
Аннотация
INTRODUCTION: Neuropeptide Y (NPY) exerts neuroprotective effects; however, its functional relationship with autophagy-related signaling pathways in AD-associated cognitive dysfunction remains insufficiently understood. Using an Aβ-induced rat model of AD, the present study evaluated the effects of NPY on learning and memory. Specifically, we examined whether pharmacological manipulation with 3-methyladenine and MHY1485 modifies the cognitive effects of NPY, providing an indirect behavioral-pharmacological assessment of processes potentially related to autophagy and mTOR signaling.
METHODS: This experimental study was conducted on 88 male Wistar rats (200-250 g) randomly divided to 11 groups (n = 8 per group). An intracerebroventricular (ICV) injection of Aβ (2 µg/µl per rat) was used to induce the AD model. NPY (10 ng /µl), MHY1485 (an mTOR activator; 2 µM), and 3-methyladenine (3-MA; an autophagy inhibitor; 300 nmol, 30 nmol, and 3 µmol) were administered via ICV injection. Cognitive performance was assessed using the passive avoidance and Y-maze tasks.
RESULTS: NPY administration significantly decreased time spent in the dark compartment (TDC), increased step-through latency (STL) in the passive avoidance task, and enhanced spontaneous alternation behavior in the Y-maze (P < 0.05). Importantly, administration of MHY1485 and 3-MA (300 nM), either alone or in combination, significantly attenuated the cognitive-enhancing effects of NPY (P < 0.05) CONCLUSION: NPY improved cognitive performance in an Aβ-induced rat model of Alzheimer's disease. Our behavioral-pharmacological findings suggest that autophagy-related signaling contributes to the memory-enhancing effects of NPY. Pharmacological modulation with 3-MA and MHY1485 provides functional evidence consistent with the potential involvement of Beclin-1- and mTOR-related signaling, although direct molecular confirmation warrants further investigation.
METHODS: This experimental study was conducted on 88 male Wistar rats (200-250 g) randomly divided to 11 groups (n = 8 per group). An intracerebroventricular (ICV) injection of Aβ (2 µg/µl per rat) was used to induce the AD model. NPY (10 ng /µl), MHY1485 (an mTOR activator; 2 µM), and 3-methyladenine (3-MA; an autophagy inhibitor; 300 nmol, 30 nmol, and 3 µmol) were administered via ICV injection. Cognitive performance was assessed using the passive avoidance and Y-maze tasks.
RESULTS: NPY administration significantly decreased time spent in the dark compartment (TDC), increased step-through latency (STL) in the passive avoidance task, and enhanced spontaneous alternation behavior in the Y-maze (P < 0.05). Importantly, administration of MHY1485 and 3-MA (300 nM), either alone or in combination, significantly attenuated the cognitive-enhancing effects of NPY (P < 0.05) CONCLUSION: NPY improved cognitive performance in an Aβ-induced rat model of Alzheimer's disease. Our behavioral-pharmacological findings suggest that autophagy-related signaling contributes to the memory-enhancing effects of NPY. Pharmacological modulation with 3-MA and MHY1485 provides functional evidence consistent with the potential involvement of Beclin-1- and mTOR-related signaling, although direct molecular confirmation warrants further investigation.