Exercise protects against visual and cognitive dysfunction in diabetic rats through BDNF signaling

Abstract

Purpose: Exercise is neuroprotective and neuroregenerative to neuronal tissues. Previously, we have shown that treadmill exercise preserves retinal function in diabetic (DM) animals (Prall et al., 2014; ARVO E-abstract 5816) and that ANA-12, a BDNF TrkB receptor antagonist, precludes these effects (unpublished data). The purpose of this study was 1) to compare the time course of visual and cognitive decline in DM and 2) to examine whether exercise could ameliorate the cognitive and visual dysfunction in an STZ rat model of DM through similar BDNF mechanisms.

Methods: Wild-type Long Evans rats were injected with streptozotocin (STZ; 100 mg/kg) to induce hyperglycemia (glucose >250 mg/dL), and were compared to non-DM controls (Ctrl). Separate DM cohorts were exercised for 30min on treadmills for 5 days/wk for 8 weeks at 0 m/min for Inactive groups or 15m/min for Active groups. To block BDNF, half of the DM rats were given either an injection of ANA-12 or vehicle 2.5 hours before exercise. Contrast sensitivity was measured at 8 wks post-STZ using a virtual optokinetic tracking system. Cognitive function was tested using a y-maze to assess spatial alternation at 7 to 9 wks post-STZ. Each rat was allowed to explore the maze for 8 min. An alternation was defined as entering all 3 arms consecutively.

Results: Contrast sensitivity was decreased by 50% in DM rats compared to Ctrl (DM: 3.86 ±0.50, Ctrl: 7.82 ±0.54 c/d, p<0.002), while cognitive function was decreased by 24% (DM: 50 ±4%, Ctrl: 66 ±3%, p<0.02). Exercise significantly preserved contrast sensitivity in DM rats (5.00 ±0.29 c/d) to an intermediate level between DM and Ctrl. In comparison, exercise significantly preserved cognitive function in DM rats to non-diabetic control levels (68 ±4%, p=0.6). ANA-12 treatment partially blocked the protective effects of exercise on contrast sensitivity (4.07 ±0.25 c/d, p=0.06) and completely blocked cognitive function (48 ±6%, p<0.01) in the DM rats.

Conclusions: DM rats had measureable visual and cognitive deficits, although larger magnitude changes were measured in contrast sensitivity. The visual and cognitive deficits present in DM animals were ameliorated with exercise with BDNF signaling mediating these protective effects; however, cognitive function showed greater benefits from exercise. Exercise is a non-invasive, low cost intervention that may provide benefit to the retina and brain of diabetic patients.