Effect of Propionic Acid on Diabetes-Induced Impairment of Unfolded Protein Response Signaling and Astrocyte/Microglia Crosstalk in Rat Ventromedial Nucleus of the Hypothalamus.

Background: The aim was to investigate the influence of propionic acid (PA) on the endoplasmic reticulum (ER), unfolded protein response (UPR) state, and astrocyte/microglia markers in rat ventromedial hypothalamus (VMH) after type 2 diabetes mellitus (T2DM). Methods: Male Wistar rats were divided: (1) control, (2) T2DM, and groups that received the following (14 days, orally): (3) metformin (60 mg/kg), (4) PA (60 mg/kg), and (5) PA+metformin. Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed. Results: We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA-by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin-by 4.98-fold, PA-5.64-fold, and metformin+PA-3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values. Conclusions: T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH.

Experimental unilateral intracerebral hemorrhage induces delayed bilateral neurodegeneration of sciatic nerve fibres in rats.

Pathological processes, such as inflammatory effects, oxidative stress, apoptosis and cytotoxicity of blood after an intracerebral hemorrhage (ICH), generally contribute to a secondary injury. One of the secondary ICH consequences in the nervous system may be delayed neurodegeneration of the peripheral nerves. Therefore, the aim of our study was to investigate possible structural changes in the sciatic nerve and changes in the conduction velocity via this nerve at different terms after experimental ICH in male Wistar rats. Intracerebral hemorrhage was provided by direct injection of autologous blood into the capsula interna. On the 10th day after ICH mean conduction velocity in sciatic nerve was 15% smaller compared to the control. On the 30th and 90th days after ICH, highly significant decreases in the conduction velocity by 62% and 60%, respectively in comparison with the control group of animals were observed. The data of morphometric analysis demonstrated significant decreases in the mean diameter and density of myelinated fibres at all examined terms after ICH. A number of the myelin sheaths were swollen and lost their regular laminations. Axoplasmic and myelin degenerations were the most frequent events in these nerve fibres; reductions of the diameter of the axis cylinders were also observed. In the contralateral nerve (related to the hemisphere with ICH), negative changes were greater, while the ipsilateral nerve was also subjected to those. Our data demonstrate that the consequences of unilateral ICH in the capsula interna induce bilateral negative changes in the peripheral nervous system of rats.

CARDIOVASCULAR SYSTEM OF THE MATURE RATS WITH CONGENITAL HYPOTHYROIDISM AND ARTERIAL HYPERTENSION.

OBJECTIVE: The aim: Studying changes in the ultrastructure of blood circulatory capillaries of the myocardium of mature rats with hypothyroidism and arterial hypertension. PATIENTS AND METHODS: Materials and methods: Experiments were conducted on (240 days) 10 ISIAH (inherited stress-induced arterial hypertension) line rats with AH (arterial hypertension), 10 Wistar line rats with congenital hypothyroidism and 10 intact animals. Arterial pressure was measured, and the development of hypothyroidism was controlled by the immune enzyme method. The study of the left ventricle myocardium of the rat heart was carried out by electron microscopic and morphometric studies. RESULTS: Results: In in rats with AH the following changes were observed in the blood capillaries of the myocardium: decrease in the number of capillaries; disturbance of blood circulation; the number of organelles of the biosynthetic plan and structures involved in the transendothelial transfer of substances decreased in endothelial cells; lysis and edema of the latter; mucinous perivascular edema, confirmed by the accumulation of fine-fibrillar structures, collagen fibers, cellular detritus. By the same term, in the group with congenital hypothyroidism, dystrophic-destructive changes in the blood capillaries of the myocardium acquired the highest degree, which resulted in a decrease in their number due to destruction. Ultrastructure of the biosynthetic plan organelles and structures of the transendothelial transfer of substances were in decompensated state. CONCLUSION: Conclusions: The rats (in 240 days) with AH and congenital hypothyroidism express breakdown of compensatory processes in the capillaries of the myocardium. This is manifested by the further dilution of capillaries, the development of hypoxic state in them as well as mucinous edema of interstitium, the decrease of activity of biosynthetic and transport processes.