The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has emerged as a promising therapeutic target for neurodegenerative diseases. AhR modulators work by regulating immune responses, particularly microglia polarization, and modulating tryptophan metabolism pathways that are dysregulated in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [1].
The aryl hydrocarbon receptor is a cytosolic receptor that, upon ligand binding, translocates to the nucleus and regulates expression of target genes including cytochrome P450 enzymes (particularly CYP1A1, CYP1A2, CYP1B1), inflammatory mediators, and cell cycle regulators [2].
Currently, several AhR-targeted approaches are in various stages of clinical development:
| Agent | Company | Indication | Phase | Status |
|---|---|---|---|---|
| Nelotanserin (AX-101) | Axial Therapeutics | PD | Phase 2 | Completed |
| BK-101 | -- | AD | Preclinical | -- |
| Resveratrol-derived AhR ligands | Various | AD/PD | Preclinical | -- |
AhR modulators have demonstrated a generally favorable safety profile in clinical trials:
Ah Receptor as a Therapeutic Target in Neurodegenerative Diseases. Cellular and Molecular Neurobiology. 2024. ↩︎
The aryl hydrocarbon receptor: A candidate for immunomodulation in neurodegeneration. Neuropharmacology. 2023. ↩︎
Microglial AhR deficiency drives α-synucleinopathy and dopaminergic neuron loss. Nature Neuroscience. 2024. ↩︎
Kynurenine pathway metabolites in neurodegenerative disorders. Progress in Neurobiology. 2023. ↩︎
Aryl hydrocarbon receptor maintains blood-brain barrier integrity. Journal of Neuroinflammation. 2023. ↩︎
AhR-mediated antioxidant response in neuronal cells. Free Radical Biology and Medicine. 2022. ↩︎
AhR activation ameliorates amyloid-β pathology in APP/PS1 mice. Alzheimer's & Dementia. 2022. ↩︎
Tau pathology reduction through AhR signaling in 3xTg-AD mice. Brain, Behavior, and Immunity. 2023. ↩︎
Neuroprotective effects of AhR ligands against amyloid-beta toxicity. Neurobiology of Disease. 2021. ↩︎
AhR agonists protect dopaminergic neurons in MPTP model of Parkinson's disease. Movement Disorders. 2022. ↩︎
Modulation of α-synuclein pathology by AhR in preclinical models. Acta Neuropathologica. 2024. ↩︎
Protective effects of AhR activation in 6-OHDA rat model. Molecular Neurobiology. 2021. ↩︎
AhR modulation extends survival in SOD1 G93A ALS mice. Annals of Clinical and Translational Neurology. 2023. ↩︎
AhR signaling and TDP-43 proteinopathy. Neurobiology of Aging. 2022. ↩︎
Clinical evaluation of AhR modulator in Parkinson's disease psychosis. ClinicalTrials.gov. 2022. ↩︎