Hyperpolarized [1-¹³C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice

Purpose: Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer’s disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is un-clear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism. Using hyperpolarized (HP) [1-¹³C]pyruvate magnetic resonance spectroscopy (MRS), this study intends to evaluate the influence of agmatine on brain metabolism. Materials and Methods: ICR mice were fed a high-fat diet and injected with streptozotocin to develop a T2DM animal model. During a 2-week period, T2DM mice were treated with normal saline or 100 mg/kg of agmatine, and brain HP [1-¹³C]pyruvate MRS was performed. The effect of agmatine on lactate generation and NADH/NAD+ redox state was investigated using C6 and neuro-2a (N2a) cells. Results: As a perfusion marker, the total¹³C signals in the brain of T2DM mice (p=0.07) and agmatine-treated mice (p<0.05) were reduced. The conversion constant (K_pl) from [1-¹³C]pyruvate to [1-¹³C]lactate was not distinguishable in the brains of T2DM mice but was significantly increased in the brains of agmatine-treated T2DM mice. Treating C6 and N2a cells with agmatine increased NADH/NAD+ ratio and lactate generation. Conclusion: Agmatine influences the NADH/NAD+ redox state in the brains of T2DM mice, which may be connected with en-hanced cognitive performance and increased conversion of HP [1-¹³C]pyruvate to HP [1-¹³C]lactate.