Insulin and α-Tocopherol Enhance the Protective Effect of Each Other on Brain Cortical Neurons under Oxidative Stress Conditions and in Rat Two-Vessel Forebrain Ischemia/Reperfusion Injury

Abstract

Clinical trials show that insulin administered intranasally is a promising drug to treat neurodegenerative diseases, but at high doses its use may result in cerebral insulin resistance. Identifying compounds which could enhance the protective effects of insulin, may be helpful to reduce its effective dose. Our aim was thus to study the efficiency of combined use of insulin and α-tocopherol (α-T) to increase the viability of cultured cortical neurons under oxidative stress conditions and to normalize the metabolic disturbances caused by free radical reaction activation in brain cortex of rats with two-vessel forebrain ischemia/reperfusion injury. Immunoblotting, flow cytometry, colorimetric, and fluorometric techniques were used. α-T enhanced the protective and antioxidative effects of insulin on neurons in oxidative stress, their effects were additive. At the late stages of oxidative stress, the combined action of insulin and α-T increased Akt-kinase activity, inactivated GSK-3beta and normalized ERK1/2 activity in cortical neurons, it was more effective than either drug action. In the brain cortex, ischemia/reperfusion increased the lipid peroxidation product content and caused Na+,K+-ATPase oxidative inactivation. Co-administration of insulin (intranasally, 0.25 IU/rat) and α-T (orally, 50 mg/kg) led to a more pronounced normalization of the levels of Schiff bases, conjugated dienes and trienes and Na+,K+-ATPase activity than administration of each drug alone. Thus, α-T enhances the protective effects of insulin on cultured cortical neurons in oxidative stress and in the brain cortex of rats with cerebral ischemia/reperfusion injury.

Protective Actions of α-Tocopherol on Cell Membrane Lipids of Paraquat-Stressed Human Astrocytes Using Microarray Technology, MALDI-MS and Lipidomic Analysis

“…It is known that tocopherol and tocotrienol compounds prevent lipid peroxidation due to their ROS scavenger properties [ 44 ], protecting unsaturated fatty acids and lipid mediators [ 31 ]. In addition, α-tocopherol regulates the expression of genes implicated in apoptosis or antioxidant defenses, such as Bcl2-L1 or γ-glutamylcystein synthetase [ 44 , 45 ], or in lipid homeostasis, such as phospholipase A2 [ 46 ], which has 1-O-acyl ceramide synthase activity, using ceramides as an acceptor [ 47 ]. Thus, we predicted that lipid changes due to Paraquat exposure can be mitigated by this antioxidant pre-treatment.…”

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

“…Despite a significant number of studies on the effects of peripheral and intracerebroventricular insulin administration to correct the consequences of cerebral ischemia, there are relatively few data on the use of INI, despite the promise of this method for correcting ischemic damage [ 186 , 187 , 188 , 189 , 190 , 191 , 192 ]. It should be noted that intranasally administered IGF-1 has been used for the correction of damage caused by cerebral ischemia–reperfusion for 20 years [ 186 , 193 , 194 , 195 , 196 , 197 , 198 , 199 ].…”

“…In 2018–2022, we carried out a set of studies on the ability of INI to influence metabolic processes and oxidative stress during bilateral global forebrain ischemia-reperfusion in rats [ 187 , 188 , 189 , 190 ]. At doses of 0.25 and 0.5 IU/rat, INI showed antioxidant and neuroprotective effects on the brain of rats with ischemia, and also prevented oxidative inactivation of Na + /K + -ATPase and accumulation of lipid peroxidation (LPO) products in the brain.…”

Profiles of Fatty Acids, Polyphenols, Sterols, and Tocopherols and Scavenging Property of Mediterranean Oils: New Sources of Dietary Nutrients for the Prevention of Age-related Diseases

“…Zakharova et al 62) also investigated the efficacy of combining insulin and α-tocopherol to increase the viability of cultured cortical neurons under oxidative stress conditions and to normalize metabolic disturbances caused by free radical reaction activation in rats with two-vessel forebrain ischemia/reperfusion injury in the brain cortex. The latter demonstrated that α-tocopherol improved the protective and antioxidative actions of insulin on neurons.…”