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.
Highlights
Olfactory sensory neurons (OSNs) are essential for odor sensing, which helps maintain a healthy lifestyle by preventing the ingestion of tainted foods and entry into dangerous environments while allowing the recognition of edible food and familiar scents
The results showed that methimazole-induced olfactory epithelium (OE) damage was inhibited by insulin administration; a higher insulin concentration resulted in a higher number of remaining OSNs, while a lower concentration resulted in a lower number of remaining OSNs
(n = 3 mice, OSNs, p = 0.36, Figure 2I; olfactory marker protein (OMP), p = 0.45, Figure 3J, Mann–Whitney U-test). These results suggest that increasing the nasal concentration of insulin prevents the induction of apoptosis by eosinophilic cationic protein (ECP), which contributes to the protective effect of nasal insulin against ECP-induced olfactory disorders
Summary
Olfactory sensory neurons (OSNs) are essential for odor sensing, which helps maintain a healthy lifestyle by preventing the ingestion of tainted foods and entry into dangerous environments while allowing the recognition of edible food and familiar scents. The accompanying eosinophilia is associated with the release of several neurotoxins, such as eosinophilic cationic protein (ECP), major basic protein, and β-glucuronidase. These substances can induce the apoptosis of OSNs, and their concentrations are quantitatively associated with olfactory dysfunction (Becker et al, 2012). When the OE is severely damaged or persistently exposed to neurotoxic substances, the olfactory impairment becomes chronic, despite the unique neural plasticity of the OE (Litvack et al, 2009; Soler et al, 2010; Whitcroft et al, 2018; Cooper et al, 2020). It is important to protect OSNs from toxic compounds and prevent pathological conditions in order to maintain olfactory function
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