A molecule best known for punching holes in bacterial membranes may have an unexpected second life as a neuroprotective agent. In a study published in Molecular Biology Reports, researchers at Erciyes University report that gramicidin A, a classical antimicrobial peptide first isolated in the 1930s, protected human neuronal cells from the kind of damage that underlies Parkinson’s disease. The findings, while still confined to laboratory dishes, add a surprising new candidate to the growing list of compounds being screened for their ability to shield vulnerable dopamine-producing neurons from oxidative destruction.
Parkinson’s disease is the fastest-growing neurological disorder in the world, and its hallmark is the progressive death of dopaminergic neurons in a region of the brain called the substantia nigra. Decades of research have converged on a central culprit: oxidative stress. When reactive oxygen species accumulate faster than cellular antioxidant defenses can neutralize them, they attack lipids, proteins, and DNA, triggering a cascade that culminates in mitochondrial failure, genomic damage, and inflammatory signaling. Because current therapies only manage symptoms rather than halt this degeneration, identifying molecules that can interrupt the damage cascade has become one of the most actively pursued goals in neurodegeneration research.
To test gramicidin A’s protective potential, the team, led by Pınar Altın-Celik and Hamiyet Donmez-Altuntas, used a widely accepted cellular model of Parkinson’s disease. They cultured SH-SY5Y cells, a human neuroblastoma line that behaves much like dopaminergic neurons, and injured them with 6-hydroxydopamine, or 6-OHDA, a toxin that selectively mimics the oxidative damage seen in Parkinson’s brains. 6-OHDA is a structural relative of dopamine that readily oxidizes, generating a flood of free radicals that devastate the cells’ antioxidant systems. The researchers then measured whether gramicidin A, applied either before the toxin as a preventive treatment or after it as a rescue treatment, could blunt the damage.
The experimental design was rigorous and multi-layered. First, an MTT viability assay established a safe working concentration of gramicidin A, ensuring that any protective effect was not simply an artifact of the peptide’s own toxicity. The team then quantified an extensive panel of stress markers: reactive oxygen species production, total antioxidant status, total oxidant status, the composite oxidative stress index, malondialdehyde as a readout of lipid peroxidation, reduced glutathione as the cell’s principal internal antioxidant, and glutathione peroxidase, the enzyme that recycles peroxides using glutathione. They also tracked mitochondrial membrane potential using the JC-10 fluorescent probe, measured 8-hydroxy-2′-deoxyguanosine, a canonical biomarker of oxidative DNA damage, and quantified the inflammatory cytokines interleukin-6, interleukin-8, and transforming growth factor-beta.
The results were striking. Exposure to 6-OHDA alone slashed cell viability, drove reactive oxygen species to dramatically elevated levels, and threw the oxidative balance into disarray, with all changes reaching high statistical significance. Malondialdehyde, which reflects the peroxidation of membrane lipids, surged, while reduced glutathione, the cell’s frontline antioxidant reserve, was depleted. In other words, the toxin recreated, in miniature, the biochemical signature of neuronal degeneration observed in Parkinson’s disease patients.
When gramicidin A was introduced, the picture changed substantially. Both pre-treatment and post-treatment protocols significantly reduced reactive oxygen species levels, restored the balance between total antioxidant and total oxidant status, lowered malondialdehyde concentrations, and boosted reduced glutathione levels. Glutathione peroxidase activity was modulated as well, suggesting that the peptide helps re-establish the glutathione-dependent peroxide disposal system rather than merely mopping up radicals directly. The consistency of the effect across both preventive and rescue schedules is particularly noteworthy, because it implies the molecule acts on the damage pathway itself rather than simply fortifying cells in advance.
The protective influence extended deep into the mitochondria and the genome. The JC-10 red-to-green fluorescence ratio, which reports on the integrity of the mitochondrial membrane potential, shifted in a direction consistent with preserved mitochondrial function in gramicidin A-treated cells. This matters because mitochondrial depolarization is both a consequence and a driver of oxidative injury: damaged mitochondria leak more reactive oxygen species, which in turn damages the mitochondria further. Levels of 8-hydroxy-2′-deoxyguanosine, the oxidized DNA base that serves as a fingerprint of oxidative genotoxic stress, also fell significantly in treated cells, indicating that gramicidin A shielded the genetic material from radical attack.
Perhaps most intriguingly, gramicidin A suppressed the inflammatory response triggered by 6-OHDA. The toxin normally drives sharp elevations in interleukin-6, interleukin-8, and transforming growth factor-beta, cytokines that propagate neuroinflammatory signaling and can amplify neuronal injury. In gramicidin A-treated cultures, these elevations were markedly and significantly blunted. Because neuroinflammation is increasingly recognized as a central amplifier of neurodegeneration, a molecule that simultaneously dampens oxidative stress, preserves mitochondrial integrity, limits DNA damage, and quiets inflammatory cytokines addresses multiple nodes of the degeneration network at once.
Gramicidin A’s mechanism of action in this context remains an open question. As an ionophore, the peptide forms channels that conduct monovalent cations across lipid bilayers, which is how it kills bacteria by collapsing their membrane gradients. How such a molecule exerts antioxidant and anti-inflammatory effects in mammalian neuronal cells is not yet clear, and the authors did not identify a specific signaling pathway responsible for the protection. The team notes that gramicidin A has previously been shown to modulate inflammation and trigger apoptosis in breast cancer cells, and that related antimicrobial peptides such as iturin A and surfactin have shown neuroprotective and anti-inflammatory properties in comparable models, suggesting a broader therapeutic potential for this class of biosurfactant-derived molecules.
The road from a culture dish to a clinic is long, and the authors are careful to frame their conclusions appropriately. These findings demonstrate that gramicidin A attenuates 6-OHDA-induced cellular injury in SH-SY5Y cells by modulating oxidative stress, mitochondrial membrane potential-related changes, oxidative DNA damage, and inflammatory stress responses, but they do not establish efficacy in living organisms. Key questions remain about bioavailability, blood-brain barrier penetration, dosing, and safety, particularly given the peptide’s membrane-disrupting history. Still, the study, supported by the Scientific and Technological Research Council of Türkiye, offers a provocative proof of concept: a molecule discovered as an antibiotic nearly a century ago may harbor the biochemical tools to defend the neurons that Parkinson’s disease destroys. As researchers continue to mine the chemical space of antimicrobial peptides for neuroprotective leads, gramicidin A has now earned a place on that shortlist.
Subject of Research: Gramicidin A attenuates oxidative stress, mitochondrial dysfunction, DNA damage, and inflammation in 6-OHDA-induced SH-SY5Y cells
Article Title: Gramicidin A attenuates oxidative stress, mitochondrial dysfunction, DNA damage, and inflammation in 6-OHDA-induced SH-SY5Y cells
Article References: Altın-Celik, P., Derya-Andeden, M., Bitgen, N., Eciroglu-Sarban, H., & Donmez-Altuntas, H. (2026). Gramicidin A attenuates oxidative stress, mitochondrial dysfunction, DNA damage, and inflammation in 6-OHDA-induced SH-SY5Y cells. Molecular Biology Reports, 53(1), Article 1758. https://doi.org/10.1007/s11033-026-12939-9
Image Credits: AI Generated
DOI: 10.1007/s11033-026-12939-9
Keywords: Gramicidin, attenuates, oxidative, stress, mitochondrial, dysfunction, damage, inflammation, OHDA-induced, SH-SY5Y, cells, scientific research
