Effect of a brain penetrant 5-HT7 receptor agonist LP-211 alone and in combination with gabapentin on cognitive deficits in insulin treated diabetic neuropathic rats

Introduction: Cognitive deficits were found to be more pronounced in diabetic neuropathic pain (DNP) patients, with limited treatment options. This study investigates the effects of 5-HT7 agonist (LP-211), alone and in conjunction with gabapentin, on cognitive deficits in insulin-treated DNP (IDNP) rats. Materials and Methods: Diabetes was induced in male rats (N=71) using streptozotocin (50 mg/kg, intraperitoneally). DNP was assessed using Von Frey and acetone tests. Selected DNP rats received insulin (2 IU/kg, subcutaneously) daily. Treatments included LP-211 (3 mg/kg), gabapentin (10 mg/kg), combination (LP-211 + gabapentin), and donepezil(1mg/kg), which were administered intraperitoneally. Cognitive performances were evaluated through novel object recognition, novel location recognition, and fear conditioning tasks. Biomarkers such as monoamines, brain-derived neurotrophic factor (BDNF), interleukin-1 beta (IL-1β), and nerve conduction velocity (NCV) were measured. Results and Discussion: Insulin maintained blood glucose levels, but did not alleviate cognitive deficits. LP-211, 3 mg/kg,donepezil, 1 mg/kg and LP-211, 3 mg/kg + gabapentin, 10 mg/kg demonstrated a significant discriminative index between novel and familiar objects, as well as object locations. Only combination treatment showed significant retrieval of percentage freezing and regulated biomarkers like NCV, monoamines, BDNF, and IL-1β levels compared to IDNP vehicle group. Donepezil modulated monoamines and BDNF, especially, LP-211, 3 mg/kg and donepezil; 1 mg/kg alone did not enhance the freezing response in IDNP rats. Overall, combination treatment notably showed enhanced associative learning, recognition, and spatial memory capabilities. Conclusion: Acute treatment with LP-211 (3 mg/kg) + gabapentin (10 mg/kg) effectively improved integrated nature of memory in IDNP rats.