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The effect of intra-nasal co-treatment with insulin and growth factor-rich serum on behavioral defects, hippocampal oxidative-nitrosative stress, and histological changes induced by icv-STZ in a rat model

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Abstract

Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus.

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Availability of data and materials

Study data and analysis are available from the corresponding author upon reasonable request.

Abbreviations

AD:

Alzheimer’s disease

APP/PS1:

A mutant amyloid precursor protein and presenilin 1 gene

BDNF:

Brain-derived neurotrophic factor

BBB:

Blood-brain barrier

CA:

Cornu Ammonis

cAMP:

Cyclic adenosine monophosphate

CREB:

CAMP response element-binding protein

DG:

Dentate gyrus

FGF2:

Basic fibroblast growth factor

GPx:

Glutathione peroxidase

GABA:

Gamma-aminobutyric acid

GFRS:

Growth factor-rich serum

HGF:

Hepatocyte growth factor

ICV:

Intracerebroventricular

IGF-1:

Insulin-like growth factor 1

MWM:

Morris water maze

MDA:

Malondialdehyde

NGF:

Nerve growth factor

NO:

Nitric oxide

OCT:

Optimal cutting temperature compound

PRP:

Platelet-rich plasma

PDGF:

Platelet-derived growth factor

sAD:

Elderly sporadic Alzheimer’s disease

SOD:

Superoxide dismutase

STZ:

Streptozotocin

TGF-B1:

Transforming growth factor beta 1

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The present article is part of a Master of Sciences thesis written by Mahdi Khorsand Ghaffari.

Funding

This research was financed by grant number SUMS-97–01-01018475, awarded to Dr. Ali Rafati from the Shiraz University of Medical Sciences, Shiraz, Iran.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mahdi Khorsand Ghaffari, Ali Rafati, Narges Karbalaei & Masoud Haghani

  2. Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Ali Rafati, Narges Karbalaei, Masoud Haghani & Mohammad Reza Namavar

  3. Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Marzieh Nemati

  4. Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Niloofar Sefati & Mohammad Reza Namavar

  5. Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Reza Namavar

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Contributions

Mahdi Khorsand Ghaffari: designing the study, performing laboratory work, data collection, and writing the manuscript draft. Ali Rafati: supervising laboratory works, conceptualization, methodology, and data analysis. Narges Karbalaei: conceptualization, methodology. Masoud Haghani: conceptualization, methodology. Marzieh Nemati: methodology, laboratory assistance, data analysis. Niloofar Sefati: methodology, laboratory assistance, graphical design. Mohammad Reza Namavar: conceptualization, methodology, data analysis, editing, and revising the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Mohammad Reza Namavar.

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All experimental procedures in the study were based on the National Institutes of Health’s Guide for Care and Use of Laboratory Animals and the Animal Research: Reporting in Vivo Experiments (ARRIVE) Guidelines and approved by the local Ethical Committee of the Shiraz University of Medical Sciences (approval number: IR.SUMS.REC.1398.168).

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Ghaffari, M.K., Rafati, A., Karbalaei, N. et al. The effect of intra-nasal co-treatment with insulin and growth factor-rich serum on behavioral defects, hippocampal oxidative-nitrosative stress, and histological changes induced by icv-STZ in a rat model. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02899-3

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