Abstract
Cognitive dysfunction is a very severe consequence of diabetes, but the underlying causes are still unclear. Recently, the cerebellum was reported to play an important role in learning and memory. Since long-term depression (LTD) is a primary cellular mechanism for cerebellar motor learning, we aimed to explore the role of cerebellar LTD pathways in diabetic rats and the therapeutic effect of gastrodin. Diabetes was induced by a single injection of streptozotocin into adult Sprague–Dawley rats. Motor learning ability was assessed by a beam walk test. Pathological changes of the cerebellum were assessed by Hematoxylin-Eosin (HE) and Nissl staining. Cellular apoptosis was assessed by anti-caspase-3 immunostaining. Protein expression levels of LTD pathway-related factors, including GluR2, protein kinase C (PKC), NR2A, and nNOS, in the cerebellar cortex were evaluated by western blotting and double immunofluorescence. The NO concentration was measured. The cellular degeneration and the apoptosis of Purkinje cells were evident in the cerebellum of diabetic rats. Protein expression levels of GluR2 (NC9W: 1.26 ± 0.12; DM9W + S: 0.81 ± 0.07), PKC (NC9W: 1.66 ± 0.10; DM9W + S: 0.58 ± 0.19), NR2A (NC9W: 1.40 ± 0.05; DM9W + S: 0.63 ± 0.06), nNOS (NC9W: 1.26 ± 0.12; DM9W + S: 0.68 ± 0.04), and NO (NC9W: 135.61 ± 31.91; DM9W + S: 64.06 ± 24.01) in the cerebellum were significantly decreased in diabetic rats. Following gastrodin intervention, the outcome of motor learning ability was significantly improved (NC9W: 6.70 ± 3.31; DM9W + S: 20.47 ± 9.43; DM9W + G: 16.04 ± 7.10). In addition, degeneration and apoptosis were ameliorated, and this was coupled with the elevation of the protein expression of the abovementioned biomarkers. Arising from the above, we concluded that gastrodin may contribute to the improvement of motor learning by protecting the LTD pathways in Purkinje cells.
Highlights
Diabetes mellitus (DM) is a multifactorial disease characterized by chronic metabolic disturbances
Since long-term depression (LTD) at the parallel fibers associated with the Purkinje cell synapses within the cerebellar cortex has been considered as a primary cellular mechanism for cerebellar motor learning (Inoshita and Hirano, 2018), we aimed to investigate the effect of diabetes on the cerebellum and the role of LTD pathways in DM-induced cognitive dysfunction
In light of the above, we suggest that gastrodin can exert its therapeutic effects on cognitive dysfunction in diabetes (CID) by reducing apoptosis of Purkinje cells as well as preserving the cerebellar LTD pathways, though the underlying protective mechanism of gastrodin on Purkinje cells remains to be explored
Summary
Diabetes mellitus (DM) is a multifactorial disease characterized by chronic metabolic disturbances. Increasing evidence has shown that diabetes can lead to cognitive dysfunction, including impairments in learning and memory (Guven et al, 2009), dysfunctions in execution (Kodl and Seaquist, 2008), and motor coordination (Cox et al, 2005). Several studies in humans and animals have shown that the cerebellum plays an important role in cognitive processing, motor learning, and memory (Gonzalez-Tapia et al, 2015; Lawrenson et al, 2018). Since long-term depression (LTD) at the parallel fibers associated with the Purkinje cell synapses within the cerebellar cortex has been considered as a primary cellular mechanism for cerebellar motor learning (Inoshita and Hirano, 2018), we aimed to investigate the effect of diabetes on the cerebellum and the role of LTD pathways in DM-induced cognitive dysfunction
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