Modulatory effects of vitamin B3 and its derivative on the levels of apoptotic and vascular regulators and cytoskeletal proteins in diabetic rat brain as signs of neuroprotection

• Published in: Biochimica et biophysica acta. General subjects Vol. 1866; no. 11; p. 130207
• Main Authors: Tykhonenko, Tetiana, Guzyk, Mykhailo, Tykhomyrov, Artem, Korsa, Victoria, Yanitska, Lesya, Kuchmerovska, Tamara
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2022
• Subjects: Apoptosis; blood serum; blood-brain barrier; brain; Brain proteins; cytoskeleton; Diabetes mellitus; gamma-aminobutyric acid; hyperglycemia; immunohistochemistry; Neurodegeneration; neurodegenerative diseases; neuroprotective effect; niacin; Nicotinamide; Nicotinoyl-gamma-aminobutyric acid (N-GABA); rats; Reactive astrogliosis; streptozotocin; Western blotting; Reactive astrogliosis; NO; eNOS; BBB; C; D; T1D; CNS; DM; DN; N-GABA; NF-κB; SD; Neurodegeneration; Nicotinoyl-gamma-aminobutyric acid (N-GABA); STZ; iNOS; NAm; Brain proteins; Diabetes mellitus; VEGF; T2D; PARP-1; GFAP; NAD; Nf-L; Nf-H; nNOS; ROS; GABA; Nicotinamide; Nf-M; Apoptosis
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130207

Beneficial effects of nicotinamide (NAm) and its derivates have been earlier shown in animal models of diabetes mellitus (DM), but the mechanisms of their neuroprotective activities are still largely unknown. The aim of the present study was to investigate if NAm and conjugate of nicotinic acid with gamma-aminobutyric acid (N-GABA) are able to modulate expression levels of apoptosis regulators, angiogenesis-related molecules, and specific cytoskeletal proteins in diabetic rat brain. After six weeks of streptozotocin induced type 1 DM, rats were daily administered either by NAm (100 mg/kg) or N-GABA (55 mg/kg) intraperitoneally for two weeks. Protein levels were assessed by western blot and immunohistochemistry. Both NAm and N-GABA down-regulated NF-κB and Bax levels in diabetic rat brain, suggesting their anti-apoptotic activities. Tested compounds normalized VEGF and nNOS contents improving pro-angiogenic signaling reduced by hyperglycemia. Western blot showed marked up-regulation of astroglial marker GFAP and lowering neurofilament protein levels in DM group, confirmed immunohistochemically, indicating the development of reactive astrogliosis as a major response to diabetes-induced neurodegeneration. NAm had no effects on GFAP and Nf-L levels in the diabetic brain, while N-GABA increased their expression. Inversely, NAm and N-GABA dramatically reduced enhanced levels of GFAP and Nf-L found in the blood serum of diabetic rats, providing for the first time strong evidence for preserving blood-brain barrier integrity by studied compounds. Thus, NAm and N-GABA may exert neuroprotective effects by decreasing pro-apoptotic regulators levels and improving expression of angiogenic and cytoskeletal proteins impaired by hyperglycemia in rat brain. •Metabolic and cellular impairments induced by diabetes lead to protein disturbances in rat brain.•Both NAm and N-GABA down-regulate crucial pro-apoptotic biomarkers, NF-κB and Bax, thus modulating signaling pathways.•Vascular complications and reactive astrogliosis are regulated by NAm and N-GABA via modulating VEGF and GFAP expression.•Loss of BBB integrity at diabetes is prevented by NAm and N-GABA, confirmed by GFAP and Nf-L levels decrease in bloodstream.•Development of neurodegenerative changes in diabetes mellitus can be reduced by NAm or N-GABA treatment.