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. 2023 Dec;31(2):135-144.
doi: 10.1007/s40199-023-00468-w. Epub 2023 Jul 1.

A neuroprotective dose of trehalose is harmless to metabolic organs: comprehensive histopathological analysis of liver, pancreas, and kidney

Affiliations

A neuroprotective dose of trehalose is harmless to metabolic organs: comprehensive histopathological analysis of liver, pancreas, and kidney

Diego Armando Morales-Carrizales et al. Daru. 2023 Dec.

Abstract

Background: Trehalose is a non-reducing disaccharide synthesized by lower organisms. It has recently received special attention because of its neuroprotective properties by stimulating autophagy in Parkinson's disease (PD) models. Therefore, evaluating whether trehalose affects metabolic organs is vital to determine its neurotherapeutic safety.

Methods: We validated the trehalose neuroprotective dosage in a PD model induced with intraperitoneal paraquat administration twice weekly for 7 weeks. One week before paraquat administration, mice were treated with trehalose in the drinking water and continued along with paraquat treatment. Histological and morphometrical analyses were conducted on the organs involved in trehalose metabolism, including the liver, pancreas, and kidney.

Results: Paraquat-induced dopaminergic neuronal loss was significantly decreased by trehalose. After trehalose treatment, the liver morphology, the mononucleated/binucleated hepatocytes percentage, and sinusoidal diameter remained unchanged in each liver lobes. Endocrine and exocrine pancreas's histology was not affected, nor was any fibrotic process observed. The islet of Langerhans's structure was preserved when analyzing the area, the largest and smallest diameter, and circularity. Renal morphology remained undamaged, and no changes were identified within the glomerular basement membrane. The renal corpuscle structure did not suffer alterations in the Bowman's space, area, diameter, circularity, perimeter, and cellularity. Besides, the renal tubular structures's luminal area and internal and external diameter were preserved.

Conclusion: Our study demonstrates that systemic trehalose administration preserved the typical histological architecture of the organs involved in its metabolism, supporting its safety as a potential neuroprotective agent.

Keywords: Kidney; Liver; Neuroprotective dose; Pancreas; Trehalose.

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Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Dopaminergic neuronal death is prevented by trehalose without affecting body weight and survival. a. Weekly miceʼs body weight. No statistically significant difference between mice’s body weight and survival was observed between groups. b. TH fluorescence intensity was quantified in three random fields. Paraquat-induced dopaminergic neuronal loss was significantly decreased by trehalose. c. Representative midbrain sections, where anti-TH IF detected dopaminergic neurons. A significant difference was considered when p < 0.05. Ctrl, control; Tre, trehalose; PQ, paraquat; Tre/PQ, trehalose/paraquat
Fig. 2
Fig. 2
Trehalose oral administration does not alter liver morphology and microcirculation. a. Representative micrographs stained with H&E showing the histology of every hepatic lobe from the control and trehalose groups. Trehalose did not modify the liver histology relative to the control. b, e. The percentage of mononucleated and binucleated hepatocytes of the centrilobular and periportal zones was determined in 3 random fields per subject. No significant difference was observed between the trehalose and the control group. c, d, f, g. The minor and major diameters of ten random sinusoids of the centrilobular and periportal zones were measured in three random fields. No significant difference was observed between the trehalose and the control group. A significant difference was considered when p < 0.05. Ctrl, control; Tre, trehalose; CL, caudate lobe; RL, right lobe; LL, left lobe; ML, medial lobe. Central vein (V), hepatic sinusoids (red dotted lines), hepatocytes (*), basophilic regions (arrows), binucleated hepatocytes (red dotted circles)
Fig. 3
Fig. 3
Trehalose administration does not affect pancreas histology and preserves connective tissue arrangement. a. Representative micrographs stained with H&E showing the pancreas histology. Pancreas histology remained unchanged after trehalose treatment, as compared to the control. b. Masson’s Trichrome staining. No changes are observed in the amount or distribution of connective tissue. c, d, e, f. The area, circularity, and minor and major diameter were measured in ten random islets of Langerhans. No significant difference was observed between the groups. A significant difference was considered when p < 0.05. Ctrl, control; Tre, trehalose. Islet of Langerhans (red dotted circle), serous acini (red dotted square), epithelial cells (*), collagen fibers (red arrows)
Fig. 4
Fig. 4
Trehalose administration does not modify glomerular architecture and tubular structure. a. Representative micrographs stained with H&E showing the renal cortex. Kidney histology remained unchanged in response to trehalose compared to the control. b. Sections stained with PAS. The GBM and tubular basal lamina remain unchanged in response to trehalose. No mesangial expansion was observed. c, d, e, f, g, h. The area of Bowmanʼs space and the renal glomerulus, the perimeter, the diameter, the circularity, and the cellularity were measured in ten random glomeruli (with vascular or urinary pole). No significant difference was observed between the groups. i, j, k, l, m, n. The luminal area and the internal and external diameters were measured in 10 randomly selected proximal convoluted tubules and ten randomly selected distal convoluted tubules (both with a circular or oval appearance). No significant difference was observed between the groups. A significant difference was considered when p < 0.05. Ctrl, control; Tre, trehalose. Renal corpuscles (black dotted circle), proximal convoluted tubules (*), distal convoluted tubules (black arrowhead)

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