Irreversible hippocampal changes induced by high fructose diet in rats

ABSTRACT

Some reports have described that a high fructose diet is associated with a deficit of hippocampus-dependent cognitive functions. In this study, we have evaluated the effects of fructose on spatial memory and molecular markers in the hippocampus and prefrontal cortex and analyzed whether those alterations are reversible. Male Wistar rats (n = 60) began their treatment during adolescence. A group was forced to drink a solution of 10% fructose for twelve weeks. Another group was subjected to the same fructose intake schedule, but later fructose was removed, and tap water was provided for four weeks. After treatments, spatial memory was evaluated with Barnes maze. Different neurogenesis, inflammation, astrocyte, and energy homeostasis markers were evaluated with immunofluorescence, ELISA, and Western blot. Changes were analyzed using two-way repeated-measures ANOVA, one-way ANOVA, and Tukeýs posthoc test (p < 0.05). Results showed that after long-term consumption of fructose, there was an impairment of spatial memory. This deficit was concomitant with the abolition of hippocampal neurogenesis and significant increases of IL-1b in the hippocampus and prefrontal cortex. Levels of COX-2 were decreased in the hippocampus. Besides, fructose induced a significant increase in GFAP and a decrease of glutamine synthetase. Likewise, energy homeostasis-associated neuropeptide orexin-A and their receptors (ORX R1 and ORX R2) were significantly increased. The spatial memory deficit, neuroinflammation, and changes in some proteinś expression were permanent one month after the fructose elimination from the diet. These results suggest that fructose induces substantial hippocampal and cortical changes, and those are irreversible after a shift in the diet.

KEYWORDS:

• Fructose
• hippocampus
• spatial memory
• neurogenesis
• glutamine synthetase
• orexin
• interleukin-1 beta
• COX-2‌

Acknowledgements

The authors thank Dr. Miguel Tapia-Rodriguez for capturing images in the confocal microscopy and Octavio Amancio-Belmont for the technical help in the Barnes maze.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval

The use of animals was approved by the Institutional Committee for Care and Use of Laboratory Animals (CICUAL-INNN). Treatments and euthanasia were carried out according to official norms for the production, care, and use of laboratory animals (NOM-062-Z00-1999).

Authorś contributions

JFC and JMM designed the study, prepared animal models for experiments, performed the experiments, and analyzed the results. PBZ designed the study, carried out the ELISA experiments, and examined the results. PA contributed to the design and execution of western blot experiments and the interpretation of the data. MMD and OPG designed the Barnes maze experiments and analyzed the results. JFP planned the research concept, prepared samples for immunofluorescence and western blot, interpreted the data and wrote the manuscript. All authors reviewed the manuscript and have approved the final version.

Additional information

Funding

This study was partially supported by grants from Consejo Nacional de Ciencia y Tecnología-Mexico (CB-258296) to PBZ and Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México PAPIIT (IN205218) (IN215218) to MMD and OPG, respectively.

Notes on contributors

Juan Fierros-Campuzano

Juan Fierros-Campuzano is a student of the Biology degree at the National Autonomous University of Mexico. His undergraduate thesis is focused on the behavioral effects of chronic fructose consumption.

Paola Ballesteros-Zebadúa

Paola Ballesteros-Zebadúa is a researcher in medical sciences focused on the study of cognitive deficits induced by radiotherapy.

Joaquín Manjarrez-Marmolejo

Joaquín Manjarrez-Marmolejo is a researcher in medical sciences with extensive experience in behavioral analysis.

Penélope Aguilera

Penélope Aguilera is a researcher in medical sciences and has worked on the molecular analysis of various brain markers.

Mónica Méndez-Diaz

Mónica Méndez-Diaz is an associate professor and researcher in the field of neurosciences.

Oscar Prospero-García

Oscar Prospero-García is a senior researcher at the Faculty of Medicine of the National Autonomous University of Mexico. He has a recognized career in neurobiology and neurosciences.

Javier Franco-Pérez

Javier Franco-Pérez is a researcher in medical sciences with expertise in neurophysiology, neurochemistry, and behavior.