Abstract
Chronic brain dyscirculation is one of the frequent type 2 diabetes mellitus (DM) complications and leads to patients' disability. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have been proven to have advantages for cardiovascular system, but their effect on the central nervous system (CNS) has not been studied enough. To study empagliflozin effect on CNS damage functional and laboratory parameters in patients with type 2 DM and, under experimental conditions, to investigate the mechanisms of the drug neurotropic effect. The clinical part of the study included patients with type 2 DM on metformin monotherapy (n=39). Patients with a target glycated hemoglobin level formed the "MET" group (n=19), in patients with a non-target glycated hemoglobin level empagliflozin was co-administered for the following 6 months (the "MET+EMPA" group, n=20). Healthy volunteers comprised the control group (n=16). The cognitive status and neuron-specific enolase (NSE) and neurofilament light chains (NLC) concentration were studied. DM was modeled in rats, thereafter the rats were treated with empagliflozin for 8 weeks. Microglia activation was assessed using anti-Iba-1 antibodies and morphological changes in neurons when stained by the Nissl method. Both in the "MET+EMPA" and the "MET" groups cognitive deficits were observed, according to the Montreal Cognitive Assessment (MOCA) (24.0 (23.0; 27.0) and 25.0 (21.0; 27.0) points) and the Mini-Mental State Examination (MMSE) (23.75 (23.0; 27.0) and 25.0 (21.0; 27.0) points). Empagliflozin therapy led to the cognitive status normalization after 6 months (26.5 (24.0; 27.0) points according to the MOCA scale and 27.5 (24.0; 28.0) points according to the MMSE). Initially, all patients had a significant increase of NSE (3.60 (2.66; 3.76) ng/ml in the "MET" group, 3.22 (2.94; 3.54) ng/ml in the "MET+EMPA» group, 2.72 (2.13; 2.72) ng/ml in the «Control» group) and NLC (4.50 (3.31; 5.56) ng/ml in the «MET» group, 5, 25 (3.75; 6.25) ng/ml in the «MET+EMPA» group comparing with 3.50 (2.25; 3.50) ng/ml in the «Control» group). Empagliflozin therapy led to a significant decrease in NLC already after 3 months (3.80 (3.25; 3.87) ng/ml), without significant influence on the NSE level. In the experiment, DM was characterized by an increased number of activated microgliocytes and destructured neurons and a decreased number of neurons with a normal structure. Empagliflozin therapy was accompanied by a decrease in the number of immunopositive microgliocytes in the CA1 zone of the hippocampus and an increase in the number of structured neurons. Type 2 diabetes mellitus is characterized by functional and biochemical changes in the central nervous system even under satisfactory glycemic control. Therapy with empagliflozin has a neuroprotective effect, manifested in an improvement in cognitive status and a decrease in NLC level. Empagliflozin reduces neuronal damage and abnormal microglial activation.
Published Version
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