Intranasal insulin ameliorates lipopolysaccharide-induced inflammation, lipid peroxidation and neurobehavioral deficits in neonatal rats
Jhanel J Greene1, Jonathan W Lee3, Marianne H Lee2, Joseph C Crosby3, Xiaoli Dai4, Norma B Ojeda3, Yi Pang3, Abhay J Bhatt3, and Lir-Wan Fan3
1Mississippi INBRE Research Scholars, Tougaloo College, Tougaloo, MS
2Mississippi INBRE Research Scholars, Mississippi College, Clinton, MS
3Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS
4Department of Anesthesiology, University of Mississippi Medical Center, Jackson, MS
Inflammation and oxidative stress play important roles in brain damage in neonatal human and animal models. Our previous studies have shown that systemic administration of lipopolysaccharide (LPS) induces brain damage and neurobehavioral dysfunction in neonatal rats, which is associated with the production of pro-inflammatory cytokines and oxidative stress. Recent studies suggest that intranasal insulin treatment could be a neuroprotective agent in adults. The objective of the current study was to determine whether intranasal insulin treatment reduces LPS-induced neurobehavioral dysfunction, brain inflammation and oxidative stress in neonatal rats. Intraperitoneal (i.p.) injections of LPS (2 mg/kg) or sterile saline were performed in postnatal day 5 (P5) SD rat pups, and human insulin (25 μg) or vehicle was administered in each nare 5 min after LPS injection. Sensorimotor behavioral tests were carried out 24 hours after LPS exposure and brain tissues were collected to determine pro-inflammatory cytokine interleukin-1β (IL-1β) and lipid peroxidation on P6. Our results showed that the intranasal insulin reduced LPS-induced sensorimotor behavioral disturbances as seen in righting reflex, negative geotaxis, wire hanging, and hind limb suspension tests at P6. Intranasal insulin also reduced LPS-induced brain inflammation as evidenced by the increase in IL-1β levels, and brain oxidative stress, as evidenced by the increase in thiobarbituric acid reactive substances (TBARS) contents. These data suggest that intranasal insulin provides a protective effect against the neonatal LPS exposure-induced sensorimotor dysfunction, brain inflammation and oxidative stress in neonatal rats, which may be associated with the neuroprotective effect of insulin. Key Words: lipopolysaccharide, intranasal insulin, sensorimotor dysfunction, neuroprotection. Supported by Mississippi INBRE Research Scholars Program, NIH grant NH/NINDS R01NS080844, and Newborn Medicine Funds from the Department of Pediatrics, University of Mississippi Medical Center.