Protective Effect of Insulin in Mouse Nasal Mucus Against Olfactory Epithelium Injury

Abstract

Insulin is present in nasal mucus and plays an important role in the survival and activity of individual olfactory sensory neurons (OSNs) via insulin receptor-mediated signaling. However, it is unclear whether insulin acts prophylactically against olfactotoxic drug-induced olfactory epithelium (OE) injury, and whether the degree of damage is affected by the concentration of insulin in the nasal mucus. The apoptosis-inducing drug methimazole was administered to the nasal mucus of diabetic and normal mice along with different concentrations of insulin. Immunohistochemical analysis was used to assess the relationship between damage to the OE and the mucus insulin concentration and the protective effect of insulin administration against eosinophilic cationic protein (ECP)-induced OE injury. Diabetic mice had lower concentrations of insulin in their nasal mucus than normal mice (diabetic vs. normal mice, p < 0.001). Methimazole administration reduced the number of OSNs in normal mice and had a more marked effect in diabetic mice. However, unilateral insulin administration prevented the methimazole-induced reduction in the number of OSNs on the ipsilateral side but not on the contralateral side (OSNs; Insulin vs. contralateral side, p < 0.001). Furthermore, intranasal ECP administration damaged the OE by inducing apoptosis (OSNs; ECP vs. contralateral side, p < 0.001), but this damage was largely prevented by insulin administration (OSNs; Insulin + ECP vs. contralateral side, p = 0.36), which maintained the number of mature OSNs. The severity of methimazole-induced damage to the OE is related to the insulin concentration in the nasal mucus (Correlation between the insulin concentration in nasal mucus and the numbers of OSNs, R2 = 0.91, p < 0.001), which may imply that nasal insulin protects OSNs and that insulin administration might lead to the development of new therapeutic agents for ECP-induced OE injury.

Intranasal insulin – effects on the sense of smell

“…horizontal basal cells are mainly responsible for the regeneration of the olfactory epithelium after severe injury (67,68) . In line with this finding stands a study performed by Kikuta et al, demonstrating that higher concentrations of insulin in nasal mucus correlated with preservation of larger amounts of OSN, and indicating a potential protective role of the peptide against olfactory epithelial damage (69) . On…”

“…As previously explained insulin may be extracellularly transferred by OSN to the olfactory bulb, which presents high amounts of insulin receptors (69) . Taking into consideration that lower sensory input may lead to atrophy of the OB, intranasal insulin also presents a promising approach to treat the shrunken olfactory bulb in a dual mechanism.…”

“…First, it protects the olfactory epithelium from injury related OSN loss, what may further preserve a sufficient sensory input. In the second mechanism intranasally administered insulin might support the formation of stable neural circuits inhibition of OB neuron apoptosis (69,70) . Studies on this topic are needed.…”

Apoptosis and turnover disruption of olfactory sensory neurons in eosinophilic chronic rhinosinusitis

“…EOS-associated pathological changes in OM observed in patients with CRS have been validated with experimental murine models of allergic CRS (Rouyar et al, 2019), eosinophilic CRS (Kagoya et al, 2021), CRSwNP induced by ECP (Kikuta et al, 2021) and IL-4 nasal drops (Hara et al, 2023), conditional expression of IL-13 in OSNs (Saraswathula et al, 2023), and allergic rhinitis (Epstein et al, 2008;Ozaki et al, 2010;Carr et al, 2012;Selvaraj et al, 2012;Sousa Garcia et al, 2017). The results of these studies are summarized in Table 1.…”

Insulin Delivery to the Brain via the Nasal Route: Unraveling the Potential for Alzheimer's Disease Therapy

“…It also functions as a growth factor hormone that maintains autophagy, cell growth, energy utilization, mitochondrial function, oxidative stress management and protein synthesis [ 7 , 25 ]. An elevated level of intranasally-administered insulin in the nasal cavity can reduce olfactotoxic drug-induced olfactory epithelium cell damage or p53-dependent apoptosis (e.g., methimazole, eosinophilic cationic protein) [ 8 , 26 , 27 ]. Yet, insulin also functions as a neuropeptide and exerts important CNS actions including controlling peripheral nerve function, neurogenesis, nerve activity, neuronal plasticity, calorie homeostasis, glucose regulation, energy balance, regulation of lipolysis in adipose tissue, synaptogenesis, synaptic remodelling, cognitive function, learning, human memory, food intake, reproduction, growth and endocrine function [ 1 , 6 , 8 , 12 , 28 – 30 ].…”