Banca de DEFESA: MARCELLE MARIANA SALES DE FRANCA

EFFECTS OF TREATMENT WITH L-CARNITINE IN RATS WITH CARDIOVASCULAR AUTONOMIC DIABETIC NEUROPATHY WHETHER OR NOT SUBMITTED TO PHYSICAL EXERCISE: A HISTOLOGICAL, BIOCHEMICAL AND IMMUNOHISTOCHEMICAL ANALYSIS

Alpha-Lipoic Acid; Physical Activity; Biochemistry; Histomorphology; Insulin; L-carnitine; Cardiac Neuropathy

Diabetic neuropathy is the most common complication of diabetes. One of its most prevalent clinical forms is autonomic neuropathy, which affects innervations in systems such as the cardiovascular system. Diabetic Cardiovascular Autonomic Neuropathy (DCAN) is associated with a high mortality rate. Its symptoms include postural hypotension and cardiac arrhythmia, among others. Treatment focuses on symptom mitigation, as no standardized therapeutic approach exists. In Brazil, alpha-lipoic acid is recommended, along with physical exercise, which is already used in diabetes management. An alternative treatment is L-carnitine, but no studies report its effects on DCAN. Therefore, the project aimed to compare the efficacy of L-carnitine and alpha-lipoic acid in treating DCAN in experimental groups undergoing physical exercise. Forty male Wistar rats, aged 90 days, were divided into eight experimental groups: sedentary non-diabetic (RS), trained non-diabetic (RTC), trained diabetic (RTD), trained diabetic with insulin (RTDI), trained diabetic with L-carnitine (RTDLC), trained diabetic with alpha-lipoic acid and insulin (RTDAI), trained diabetic with L-carnitine and insulin (RTDLCI), and trained diabetic with alpha-lipoic acid, L-carnitine, and insulin (RTDALCI). Diabetes was induced using a streptozotocin solution, with diabetic neuropathy confirmed via hyperalgesia tests over six weeks. Animals were then adapted and subjected to a swimming protocol (5 days/week for 4 weeks). Treatments with alpha-lipoic acid (100 mg/kg) and L-carnitine (100 mg/kg) were administered by gavage, while insulin (4 U/day) was administered subcutaneously, both 7 days/week. Analyses included systolic blood pressure (SBP), anthropometry, organosomatic index, histopathology, morphometry, immunohistochemistry, cardiac injury markers, and oxidative stress. Diabetic animals exhibited higher initial SBP values compared to the RS and RTC groups. However, at the final SBP assessment, diabetic animals treated with insulin, L-carnitine, and alpha-lipoic acid, alone or in combination, had values comparable to the RS and RTC groups. Anthropometric evaluations showed weight loss in diabetic animals, but by the end of treatment, only the RTD group had significant differences compared to others. The reduced body weight consequently increased the organosomatic index. IL-6 and TNFα analyses revealed that treatments reduced the expression of these pro-inflammatory cytokines, with the most notable results in the RTDLCI and RTDALCI groups. Regarding cardiac injury markers (total CK, CK-MB, relative CK-MB index, and LDH), values in groups treated with insulin, L-carnitine, and alpha-lipoic acid were not statistically different from those of the RS and RTC groups, except for cTnI, where only the RTD group was reactive. In conclusion, L-carnitine, whether alone or in combination with alpha-lipoic acid and/or insulin, yielded positive results across all analyses. The L-carnitine/insulin combination notably enhanced GSH expression, while physical exercise alone showed no benefits in diabetic rats. Further research on antioxidant-drug interactions is warranted to advance DCAN therapy.