Asthma Drug Montelukast Shields Nerve Cells from Parkinson-Like Damage in Lab Study

In a new open-access study published on 9 October 2026 in the journal Discover Neuroscience, researchers report that pre-treating human SH-SY5Y neuroblastoma cells with montelukast before exposing them to rotenone blunted a cascade of cellular damage spanning oxidative stress, inflammation, mitochondrial dysfunction and the loss of key dopaminergic markers. The findings, drawn entirely from cell culture experiments, add to a growing body of work exploring whether an old, well-tolerated drug can be repurposed for a devastating neurodegenerative condition.

The research team, led by Apurva Chittoda and Rakesh Kumar Singh, set out to probe the role of the cysteinyl leukotriene receptor 1, or CysLTR1, in Parkinson’s disease pathology. Cysteinyl leukotrienes are inflammatory signalling molecules best known for their part in airway disease, and montelukast works by blocking the CysLTR1 receptor. But the receptor has also been implicated in central nervous system disorders, largely through its influence on microglial activation, the brain’s resident immune response. Previous studies had shown neuroprotective effects of montelukast in models of Alzheimer’s disease, cerebral ischemia, multiple sclerosis and seizures, yet its effects on rotenone-induced cellular inflammation, mitochondrial fission and dopaminergic biomarkers remained unclear.

Rotenone, a naturally occurring insecticide derived from the roots of plants in the Fabaceae family, is a mainstay of experimental Parkinson’s research. It induces redox stress, mitochondrial dysfunction and the loss of dopaminergic neurons in ways that closely mirror key neurodegenerative processes seen in the human disease. In the new study, the researchers first used an MTT viability assay to establish safe working concentrations. Rotenone reduced cell viability in a concentration-dependent manner across the range tested, from 0.1 to 10 micromolar, and the team selected 0.3 micromolar as a sub-lethal dose that induced measurable cellular perturbation without wholesale cytotoxicity. Montelukast itself showed a favourable safety profile, leaving cell viability above 90 percent across the concentrations selected for further experiments.

The experimental design was straightforward but layered. SH-SY5Y cells, a human neuroblastoma line commonly used to model dopaminergic neurons, were pre-treated with montelukast at either 1 or 10 micromolar for two hours before rotenone at 0.3 micromolar was added for a further 24 hours. The researchers then measured a battery of biochemical and molecular endpoints across three independent experiments, using ELISA kits for inflammatory cytokines, colorimetric and fluorescence assays for oxidative stress markers, western blotting for signalling proteins, and immunocytochemistry for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis.

The oxidative stress results were among the clearest. Rotenone exposure markedly increased malondialdehyde, a marker of lipid peroxidation, and boosted the generation of reactive oxygen species, both measured relative to untreated cells with high statistical significance. Pre-treatment with montelukast at both 1 and 10 micromolar substantially counteracted these changes, restoring MDA and ROS levels toward baseline. The drug also rescued the cellular antioxidant system: rotenone depleted reduced glutathione and suppressed catalase activity, and montelukast pre-treatment restored both, with the higher dose producing the stronger effect. These findings suggest the drug can meaningfully shore up the cell’s first line of defence against oxidant damage.

Underlying this antioxidant rescue, the researchers traced a specific molecular mechanism. Under normal conditions, the transcription factor NRF2 is held inactive by its binding partner KEAP1; when cellular stress strikes, NRF2 is released, moves to the nucleus and switches on genes for antioxidant defence, including glutathione synthesis and superoxide dismutase activity. Rotenone sharply diminished NRF2 protein abundance while elevating KEAP1, a signature of a compromised antioxidant regulatory axis. Montelukast pre-treatment reversed both changes, restoring NRF2 and suppressing KEAP1 in a dose-related fashion. The authors suggest that montelukast may act as an NRF2 activator, possibly by interfering with KEAP1-mediated degradation of NRF2 or by modulating upstream oxidative stress pathways, consistent with earlier reports linking CysLT1 receptor blockade to NRF2 signalling.

Inflammation and mitochondrial dynamics formed the second pillar of the findings. Rotenone significantly increased the release of the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, and montelukast pre-treatment markedly reduced these effects, with TNF-alpha significantly decreased at both doses. On the signalling level, rotenone elevated the phosphorylation of p38 mitogen-activated protein kinase and its downstream target MAPKAPK2, a cascade implicated in neuronal inflammation and apoptosis. Montelukast attenuated this activation, with the 10 micromolar dose producing the strongest suppression of phosphorylated MAPKAPK2. The drug also reduced rotenone-driven upregulation of dynamin-related protein 1, or DRP1, a central mediator of mitochondrial fission whose excess activity is associated with excessive mitochondrial fragmentation, reduced energy production and neuronal degeneration in Parkinson’s disease.

Perhaps most striking were the effects on classical Parkinson’s disease biomarkers. Rotenone exposure reduced tyrosine hydroxylase expression, confirmed both by immunofluorescence imaging and western blotting, and montelukast pre-treatment restored TH levels dose-dependently, with the 10 micromolar dose showing a highly significant recovery. The toxin also raised alpha-synuclein, the protein whose insoluble aggregates are a pathological hallmark of Parkinson’s disease, and montelukast mitigated this accumulation in a dose-related fashion. PARK7, also known as DJ-1, a neuroprotective protein tied to antioxidant defence, was markedly downregulated by rotenone and restored by montelukast at both doses. Finally, rotenone elevated CysLTR1 expression itself, and montelukast, true to its pharmacological identity as a CysLTR1 antagonist, reduced the receptor’s expression at both concentrations tested.

The authors conclude that CysLTR1-p38-MAPKAPK2/NRF2-KEAP1 constitutes a novel axis targeted by montelukast in Parkinson’s disease pathology, and they frame the results as supporting the potential repurposing of the drug. Repurposing approved medications carries real advantages, including lower costs, shorter development timelines and established safety profiles, and montelukast has already been examined in humans in this context: data from a Phase II unblinded clinical trial in patients with Parkinson’s disease showed that the drug reduced microglial activity as measured by PET imaging.

Important limitations temper the excitement. All results come from a single human neuroblastoma cell line exposed to a toxin for 24 hours, with three independent experiments per endpoint; the model captures selected facets of Parkinson’s biology but cannot reproduce the progressive, multi-system nature of the disease in patients. The rotenone dose chosen was deliberately sub-lethal, and the protective effects were measured against that specific insult. Whether montelukast reaches relevant concentrations in the human brain, whether the same signalling axis operates in living dopaminergic neurons, and whether the biomarker changes observed in culture translate into preserved neuronal function in patients all remain open questions. Still, the convergence of antioxidant, anti-inflammatory, mitochondrial and protein-aggregation effects in a single, widely available asthma drug makes this a mechanism worth pursuing in more demanding preclinical models.

Subject of Research: Neuroprotective effects of montelukast in a rotenone-induced cellular model of Parkinson's disease

Article Title: Montelukast protects against rotenone-induced neurotoxicity in human neuroblastoma cells through regulation of the p38MAPK signaling pathway

Article References: Chittoda, A., Pandey, S. K., Shukla, S., Singh, S., Ahmed, S., & Singh, R. K. (2026). Montelukast protects against rotenone-induced neurotoxicity in human neuroblastoma cells through regulation of the p38MAPK signaling pathway. Discover Neuroscience, 21(1), Article 112. https://doi.org/10.1186/s13064-026-00342-w

Image Credits: AI Generated

DOI: 10.1186/s13064-026-00342-w

Keywords: montelukast, Parkinson's disease, rotenone, SH-SY5Y cells, CysLTR1, p38 MAPK, NRF2, oxidative stress, mitochondrial fission, alpha-synuclein, drug repurposing, neuroinflammation