Overcoming Translational Barriers in Neuroprotection: From Molecular Targets to Biomarkers

Neuroprotection encompasses strategies aimed at preserving neuronal structure and function by mitigating pathological processes such as oxidative stress, excitotoxicity, neuroinflammation, and regulated cell death (RCD). Despite promising preclinical findings, translation to clinical success has been limited due to pharmacokinetic constraints, inadequate blood-brain barrier (BBB) penetration, methodological deficiencies, and a lack of objective biomarkers. Key mechanistic targets include mitochondrial stabilization, modulation of glutamate-induced calcium overload, suppression of proinflammatory glial activation, and inhibition of specific RCD pathways such as necroptosis (RIPK1/RIPK3/MLKL) and ferroptosis (GPX4/ALOX-15). Advanced in vitro platforms—including iPSC-derived organoids and co-culture systems—and rigorously designed in vivo models are essential for mechanistic validation and prediction of clinical efficacy. Translational success further relies on achieving therapeutically relevant unbound drug concentrations in the CNS (Cu,br) and integrating clinically validated biomarkers (e.g., plasma NfL, GFAP) into preclinical endpoints. Emerging therapeutic strategies encompass CNS-penetrant small molecules, biologics, cell-derived extracellular vesicles, and phytochemicals delivered via advanced formulations. This review emphasizes the necessity of mechanism-specific, biomarker-driven, and rigorously validated approaches to overcome historical translational failures and realize clinically effective neuroprotective interventions.

Neuroprotection, Regulated Cell Death, Necroptosis, Ferroptosis, Oxidative Stress

1. Verma M, et al. Excitotoxicity, calcium and mitochondria: a triad in synaptic dysfunction. Front Aging Neurosci. 2022;14:878812. doi:10.3389/fnagi.2022.878812. [Google Scholar] [Crossref]

2. Dash UC, et al. Oxidative stress and inflammation in the pathogenesis of neurodegenerative diseases. Science Progress. 2025;108(1):003685042211074. doi:10.1177/003685042211074. [Google Scholar] [Crossref]

3. Wu W, et al. Molecular mechanisms of excitotoxicity and their relevance to neurodegenerative diseases. Signal Transduct Target Ther. 2025;10(1):1–14. doi:10.1038/s41401-025-01576-w. [Google Scholar] [Crossref]

4. Cui J, et al. Regulated cell death: discovery, features and implications for neurodegenerative diseases. Biosignaling Funct Genomics. 2021;22(2):1–15. doi:10.1186/s12964-021-00799-8. [Google Scholar] [Crossref]

5. Jurcău MC, et al. The link between oxidative stress, mitochondrial dysfunction, and neurodegeneration. Antioxidants (Basel). 2022;11(11):2167. doi:10.3390/antiox11112167. [Google Scholar] [Crossref]

6. Dirnagl U, Endres M. Translational stroke research: vision and reality. Stroke. 2014;45(4):1296–1302. doi:10.1161/STROKEAHA.114.003959. [Google Scholar] [Crossref]

7. Macleod MR, et al. Good laboratory practice: preventing introduction of bias at the bench. Stroke. 2008;39(10):2825–2830. doi:10.1161/STROKEAHA.108.516044. [Google Scholar] [Crossref]

8. Savitz SI, et al. Translational strategies for neuroprotection in acute ischemic stroke. Nat Rev Neurol. 2017;13:258–270. doi:10.1038/nrneurol.2017.37. [Google Scholar] [Crossref]

9. Ghosh S, Basu A. Preclinical models of neurodegeneration: challenges and opportunities. Front Neurosci. 2021;15:654951. doi:10.3389/fnins.2021.654951. [Google Scholar] [Crossref]

10. O’Collins VE, et al. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59(3):467–477. doi:10.1002/ana.20741. [Google Scholar] [Crossref]

11. Fisher M, Saver JL. Future directions of neuroprotection in acute ischemic stroke. Stroke. 2015;46(4):1167–1173. doi:10.1161/STROKEAHA.114.007004. [Google Scholar] [Crossref]

12. Wen P, et al. Oxidative stress and mitochondrial impairment: key drivers of neurodegeneration. Neurochem Int. 2025. Available from: https://www.sciencedirect.com/. [Google Scholar] [Crossref]

13. Biswas K, et al. A review on the cell signaling pathways involved in microglial activation and neuroinflammation. J Neuroinflammation. 2023. Available from: https://pubmed.ncbi.nlm.nih.gov/. [Google Scholar] [Crossref]

14. Fei Y, et al. The role of ferroptosis in neurodegenerative diseases. Front Neurosci. 2024; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

15. Catalani E, et al. Targeting mitochondrial dysfunction and oxidative stress in retinal pathologies linked to retinal ganglion cell degeneration. Front Mol Biosci. 2023; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

16. Khan S, et al. Excitotoxicity, oxytosis/ferroptosis, and neurodegeneration. Front Neurosci. 2024; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

17. Gao C, et al. Microglia in neurodegenerative diseases: mechanism and therapeutic implications. Front Aging Neurosci. 2023; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

18. Zong Y, et al. Mitochondrial dysfunction: mechanisms and advances in therapeutic strategies. Nat Rev Neurol. 2024; Available from: https://www.nature.com/. [Google Scholar] [Crossref]

19. Ye K, et al. The double-edged functions of necroptosis in neurodegeneration. Cell Death Dis. 2023; Available from: https://www.nature.com/. [Google Scholar] [Crossref]

20. Zheng X, et al. Ferroptosis: a novel regulated cell death participating in neurodegeneration. Environ Health Prev Med. 2023; Available from: https://ehoonline.biomedcentral.com/. [Google Scholar] [Crossref]

21. Nam D, et al. Effects of calcium ion dyshomeostasis and neuroinflammation in neurodegenerative diseases. Front Neurosci. 2024; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

22. Webber EK, et al. Cytosolic calcium: judge, jury, and executioner of neurodegeneration. Alzheimers Dement. 2023; Available from: https://alz-journals.onlinelibrary.wiley.com/. [Google Scholar] [Crossref]

23. Xu Y, et al. New insight on microglia activation in neurodegenerative diseases. Front Neurosci. 2023; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

24. Liu Y, et al. The research landscape of ferroptosis in neurodegenerative diseases. Front Neurosci. 2024; Available from: https://www.frontiersin.org/. [Google Scholar] [Crossref]

25. Friedrich B, Lindauer U. Procedural and methodological quality in preclinical stroke research – a cohort analysis of the rat MCAO model comparing periods before and after the publication of STAIR/ARRIVE. Front Neurol. 2022;13. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9190283/. [Google Scholar] [Crossref]

26. Dunkel P, et al. Clinical utility of neuroprotective agents in neurodegenerative diseases: current status of drug development for Alzheimer’s, Parkinson’s, Huntington’s, and ALS. Expert Opin Investig Drugs. 2012;21(9):1267–1308. [Google Scholar] [Crossref]

27. Di Marco S, et al. Drug metabolism and pharmacokinetics, the blood-brain barrier, and CNS drug discovery. Front Pharmacol. 2021;12. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8280005/. [Google Scholar] [Crossref]

28. O’Collins VE, Macleod MR. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models. Stroke. 2007;38(4):1121–1125. doi:10.1161/01.STR.0000251427.00957.17. [Google Scholar] [Crossref]

29. Percie du Sert N, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18(7):e3000411. doi:10.1371/journal.pbio.3000411. [Google Scholar] [Crossref]

30. Rauf A, et al. Implications of iron in ferroptosis, necroptosis, and pyroptosis as potential players in TBI morbidity and mortality. J Inflamm Res. 2023;16:1967–1977. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11529200/. [Google Scholar] [Crossref]

31. Zhuo J, et al. Targeting ferroptosis for neuroprotection: potential therapeutic avenues in neurodegenerative and neuropsychiatric diseases. Acta Neuropathol Commun. 2024;12(1):41. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12423104/. [Google Scholar] [Crossref]

32. Minnella A, et al. Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for Parkinson's disease. PLoS One. 2024;19(4):e0309893. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0309893. [Google Scholar] [Crossref]

33. Thapa K, et al. Therapeutic insights on ferroptosis in Parkinson's disease. Eur J Pharmacol. 2022;930:175184. Available from: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1407335/full. [Google Scholar] [Crossref]

34. Park S, Mook-Jung I. Brain organoids are new tool for drug screening of neurological diseases. BMB Rep. 2021;54(8):411–420. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8341697/. [Google Scholar] [Crossref]

35. Durens M, et al. High-throughput screening of human induced pluripotent stem cell-derived brain organoids. J Vis Exp. 2020;(161). Available from: https://www.researchgate.net/publication/339033922_High-throughput_screening_of_human_induced_pluripotent_stem_cell-derived_brain_organoids. [Google Scholar] [Crossref]

36. Takhsha A, et al. Neuroprotective potential of phytochemicals. Front Biosci (Elite Ed). 2011;3(4):1142–1163. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3459459/. [Google Scholar] [Crossref]

37. Ahangari G, et al. Quercetin protects blood-brain barrier integrity and maintains microvascular permeability following traumatic brain injury. J Neurosurg Anesthesiol. 2025;37(2):224–231. Available from: https://pubmed.ncbi.nlm.nih.gov/40739078/. [Google Scholar] [Crossref]

38. Rzeska Z, et al. Much more than nutrients: the protective effects of nutraceuticals on the blood–brain barrier in diseases. Nutrients. 2025;17(5):766. Available from: https://www.mdpi.com/1999-4923/17/5/766. [Google Scholar] [Crossref]

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