Ishmam Alam

Background: Major depressive disorder is the fourth most prevalent global disease, and can significantly impact an individual’s daily life, potentially proliferating into suicide ideation and attempts.¹ This disorder affects a significant portion of the population, with the World Health Organization reporting a global lifetime prevalence of 10%.² Primary explanations for depression include the monoamine hypothesis, chronic overactivity of the hypothalamo-pituitary-adrenal axis or inflammation, and environmental factors.^2-4. There are various treatments for patients with depression, mainly cognitive behavioral therapy, medications, and electroconvulsive therapy.² Approximately 15-30% of patients with depression have not responded to two different medications, and are known as having treatment resistant depression (TRD).² One of the challenges in treating depression is drug delivery beyond the blood brain barrier (BBB).⁵ Cell penetrating peptides (CPPs) have been shown to bypass the BBB and perform targeted drug delivery.^5-6

 Objective: In this narrative review, we assessed the methods and efficacy of cell penetrating peptides in delivering antidepressant drugs to the brain.

Search Methods: An online search in the PubMed and Google Scholar databases were conducted from 2017 to 2023 using the following search terms: “cell penetrating peptides,” “depression,” “antidepressant,” “drug delivery,” “oxidative stress.”

Results: Various drugs and cell penetrating peptides were found to have enhanced penetration of the blood brain barrier and have modulating effects on the pathogenesis of depression. Biliverdin conjugated with Tat (Tat-BLVRA) had increased permeability into hippocampal neuronal cells.⁷ Sulpiride conjugated with the peptide VPALR (VPALR-Sul) also displayed increased BBB penetration, in addition to higher antidepressant activity.^1. Glucagon-like peptide 2 (GLP-2), when conjugated to both a CPP and a penetration-accelerating sequence (PAS), was found to have higher anti-depressant effects than GLP-2 alone.^5-6 Additionally, some of the conjugated drugs displayed reduced side effects. VPALR-Sul displayed lower serum prolactin levels, inflammation, neural apoptosis and organ toxicity.¹ Another drug, Dyro 1, bypasses the DRD1 receptor, preventing over-sensitization that causes drug-induced dyskinesia.⁸ Intranasal administration of GLP-2-CCP-PAS showed similar amounts of efficacy to intracerebroventricular administration at the same doses.^5-6 Lastly, certain CPPs had an increased protective effect against inflammation. Tat-BLVRA reduced amounts of Iba-1 and GFAP, and VPALR-Sul lowered amounts of lipopolysaccharide induced IL-1B and TNF-a, indicating decreased brain inflammation or damage.

Conclusion: Studies have shown that CPPs may increase the ability of drugs to penetrate the blood brain barrier, allowing for higher efficacy. Since CPPs allow for more targeted approaches, therapies are less likely to display side effects. Additionally, the increase in efficacy suggests that intranasal CPPs may be used as a viable alternative to more invasive methods of administering drugs. The anti-inflammatory effects of CPPs may also contribute to anti-depressive properties. Cell penetrating peptides prove to be a promising technology that may provide therapy to those with treatment resistant depression.

Works Cited:

1. Liang Y, Yang Y, Huang R, et al. Conjugation of sulpiride with a cell penetrating peptide to augment the antidepressant efficacy and reduce serum prolactin levels. Biomed Pharmacother. 2024;174:116610. doi:10.1016/j.biopha.2024.116610
2. Marx W, Penninx BWJH, Solmi M, et al. Major depressive disorder. Nat Rev Dis Primers. 2023;9(1):44. Published 2023 Aug 24. doi:10.1038/s41572-023-00454-1
3. Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model – are we there yet?. Behav Brain Res. 2018;341:79-90. doi:10.1016/j.bbr.2017.12.025
4. Lee CH, Giuliani F. The Role of Inflammation in Depression and Fatigue. Front Immunol. 2019;10:1696. Published 2019 Jul 19. doi:10.3389/fimmu.2019.01696
5. Sasaki-Hamada S, Nakamura R, Nakao Y, et al. Antidepressant-like effects exerted by the intranasal administration of a glucagon-like peptide-2 derivative containing cell-penetrating peptides and a penetration-accelerating sequence in mice. Peptides. 2017;87:64-70. doi:10.1016/j.peptides.2016.11.013
6. Akita T, Kimura R, Akaguma S, et al. Usefulness of cell-penetrating peptides and penetration accelerating sequence for nose-to-brain delivery of glucagon-like peptide-2. J Control Release. 2021;335:575-583. doi:10.1016/j.jconrel.2021.06.007
7. Kim SJ, Shin MJ, Kim DW, Yeo HJ, Yeo EJ, Choi YJ, Sohn EJ, Han KH, Park J, Lee KW, et al. Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling. International Journal of Molecular Sciences. 2020; 21(8):2672. https://doi.org/10.3390/ijms21082672
8. Lorenzon, N., Gestin, M. & Langel, Ü. Mimicry of Dopamine 1 Receptor Signaling with Cell-Penetrating Peptides. Int J Pept Res Ther 27, 83–90 (2021). https://doi.org/10.1007/s10989-020-10066-y