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234 AboEl-Azm et al. | Journal of Clinical and Translational Research 2023; 9(4): 222-235
cause discontinuation). In addition, Cognitive assessment using [2] Kazkayasi I, Telli G, Nemutlu E, Uma S. Intranasal
ADAS-Cog showed no significant improvement in either dose Metformin Treatment Ameliorates Cognitive Functions
(20 IU or 40 IU) compared with the placebo. Nonetheless, our Via Insulin Signaling Pathway in ICV-STZ-induced Mice
study found that intranasal insulin delivered at 20 IU improved the Model of Alzheimer’s Disease. Life Sci 2022;299:120538.
ADAS-Cog, but not at 40 IU. This cognitive change in response to [3] Akel H, Csóka I, Ambrus R, Bocsik A, Gróf I,
low-dosage intranasal insulin was related to neuronal extracellular Mészáros M, et al. In Vitro Comparative Study of Solid
vesicles (EV) biomarkers of insulin resistance (pS312-IRS-1, pY- Lipid and PLGA Nanoparticles Designed to Facilitate Nose-
IRS-1), suggesting activation of the insulin signaling cascade at to-brain Delivery of Insulin. Int J Mol Sci 2021;22:13258.
the IRS-1 level. [4] Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A.
4.1. Limitations and strengths of the study Insulin in the Brain: Sources, Localization and Functions.
Mol Neurobiol 2013;47:145-71.
The major limitation of this study included: The inability [5] Maher MA, Kandeel WA, Hammam OA, Attia YM,
to perform a meta-analysis of five of the included studies due Mahmoud S, Salah M. Histopathological Evaluation of
to several variations between these articles, such as reporting Insulin-DMSO Formula Designed for Direct Nose-to-brain
different outcomes utilizing various scores and some discrepancies Delivery. Histol Histopathol 2021;37:431-9.
in the duration of intervention. Future research is warranted to [6] Bazrgar M, Khodabakhsh P, Dargahi L, Mohagheghi F,
explore the efficacy of intranasal insulin in a larger sample with Ahmadiani A. MicroRNA Modulation is a Potential
longer follow-ups, taking into consideration the apoE4 status and Molecular Mechanism for Neuroprotective Effects
the progressive neurodegeneration that occurs over many years of Intranasal Insulin Administration in Amyloid βeta
and needed longer duration studies. Oligomer Induced Alzheimer’s Like Rat Model. Exp
Nevertheless, the strengths of our study are as follows: (1) Our Gerontol 2022;164:111812.
meta-analysis represented the last updated evidence assessing the [7] Page MJ, McKenzie JE, Bossuyt PM, Boutron I,
efficacy and safety of intranasal insulin in patients with AD, (2) we Hoffmann TC, Mulrow CD, et al. The PRISMA 2020
provided a more comprehensive analysis in an attempt to solve the Statement: An Updated Guideline for Reporting Systematic
previous conflicting findings, and (3) we complied the PRISMA Reviews. BMJ 2021;372:n71.
checklist when representing this manuscript and conducted all [8] Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS,
steps as stated in the Cochrane Handbook in our review.
Boutron I, et al. RoB 2: A Revised Tool for Assessing Risk
5. Conclusion of Bias in Randomised Trials. BMJ 2019;366:l4898.
[9] Claxton A, Baker LD, Wilkinson CW, Trittschuh EH,
Ultimately, the current results of intranasal insulin are Chapman D, Watson GS, et al. Sex and ApoE Genotype
encouraging in terms of safety and efficacy. Our findings Differences in Treatment Response to Two Doses of
demonstrate that the administration of lower doses (20 IU) has Intranasal Insulin in Adults with Mild Cognitive Impairment
distinctly more efficacy than higher doses (40 IU) as revealed by or Alzheimer’s Disease. J Alzheimers Dis 2013;35:789-97.
the ADAS-cog scale. To learn about the variations (sex, age, and [10] Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA,
ApoE4 carriage) in treatment responses and make the most of et al. Safety, Efficacy, and Feasibility of Intranasal Insulin
this intervention, further trials are required. In addition, a future for the Treatment of Mild Cognitive Impairment and
investigation should require reliable insulin delivery devices with Alzheimer Disease Dementia: A Randomized Clinical
proven capacity to increase insulin in the CNS.
Trial. JAMA Neurol 2020;77:1099-109.
Acknowledgments [11] Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS,
Claxton A, et al. Intranasal Insulin Therapy for Alzheimer
None. Disease and Amnestic Mild Cognitive Impairment: A Pilot
Funding Clinical Trial. Arch Neurol 2012;69:29-38.
[12] Rosenbloom M, Barclay TR, Kashyap B, Hage L,
None. O’Keefe LR, Svitak A, et al. A Phase II, Single-center,
Conflicts of Interest Randomized, Double-blind, Placebo-controlled Study of
the Safety and Therapeutic Efficacy of Intranasal Glulisine
All authors have no conflicts of interest. in Amnestic Mild Cognitive Impairment and Probable
Mild Alzheimer’s Disease. Drugs Aging 2021;38:407-15.
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