Differential effects of olfactory toxicants on olfactory regeneration

Abstract

The aim was to study the long-term response in the olfactory mucosa of NMRI mice after exposure to the olfactory toxicants dichlobenil (a herbicide) or methimazole (an antithyroid drug). Three and six months after exposure to dichlobenil (2x or 1 x 25 mg/kg i.p.), the dorsomedial part of the olfactory region showed a respiratory metaplasia with abundant invaginations and a fibrotic lamina propria. In contrast, 3 months after exposure to a toxic dose of methimazole (2 x 50 mg/kg i.p.), the olfactory neuroepithelium and lamina propria had been restored. To study the regenerative events, we used an antibody derived against growth-associated protein 43 (GAP-43), which stains immature neurons. To study epithelial differentiation and horizontal basal cells (HBCs) we used an antibody derived against some cytokeratins. Two weeks after methimazole treatment, there was a marked increase of GAP-43-stained cells in the whole olfactory region, which correlated with the observed regeneration at that time. Two weeks after dichlobenil treatment, the damaged atypical epithelium in the olfactory region showed a distinct keratin staining of basal and columnar cells whereas GAP-43-stained cells were not found. Despite a transient increase of GAP-43-stained cells in the border zone between damaged and undamaged olfactory mucosa, an expansion of a normal neuroepithelium into the damaged olfactory region was not detected in the dichlobenil-treated mice. An intact lamina propria is suggested as a prerequisite for repopulation of the neuroepithelium after toxicant-induced injury.

Odor Memory Stability after Reinnervation of the Olfactory Bulb

“…At the OE level, the dorso-ventral organization of the different OSNs populations is completely restored [45]. However, these methods damage the LP and produce metaplasia of supportive tissue of the OE [5], [6]. At the OB, few axon fibers reach the dorsal part [5] and the specific glomerular organization is disrupted [36], [37].…”

“…Previous studies have demonstrated that methimazole is metabolized by a cytochrome P450 in sustentacular cells and Bowman glands, causing massive apoptosis and promoting the degeneration of OE supportive cells [6], [51], [52]. This leads to detachment of OSNs while progenitor cells remain intact [53].…”

“…This leads to detachment of OSNs while progenitor cells remain intact [53]. Contrary to other methods, methimazole lesions induce minimal damage to the LP with no evident metaplasia of the OE [6]. The structure of the LP has an important role in axon navigation in the olfactory system.…”

“…Here, we used the anti-thyroid drug methimazole to induce degeneration of the OE in knock-in mice expressing genetic markers for the M72 and I7 receptors (M72-IRES-tau-LacZ and I7-IRES-tau-GFP). Contrary to other models of degeneration [6], methimazole preserves the integrity of the lamina propria (LP) and cribriform plate, which are essential for sensory axon fasciculation and extension during re-innervation of the bulb. We analyzed the regenerative capability of OSN populations as well as the precision of glomerular re-innervation, and examined the functional implications of glomerular circuitry regeneration for learned and innate olfactory behavior.…”

A lifetime of neurogenesis in the olfactory system

“…Indeed, recovery from zinc sulfate lesion was less efficient in adult (6 month old) mice than in young (1 month old) mice (Ducray et al, 2002a), but functional recovery occurred even in the adult group (Ducray et al, 2002b). However, chemical lesions are not equivalent in the amount of damage they cause (Bergman et al, 2002). Using a different lesion method (3,3′-iminodipropionitrile; IDPN), Genter and Ali (1998) demonstrated that there is an age-related susceptibility to damage caused by IDPN, perhaps confounding the interpretation of chemical lesion results in aged mice (Bovetti et al, 2011).…”