Tetracyclines and their Non-Antibiotic Derivatives: Therapeutic Potential in Neurodegeneration and Neuronal Dysfunction

Neurodegenerative disorders arise from interconnected pathological cascades involving neuroinflammation, protein misfolding, and progressive neuronal dysfunction. These processes, often exacerbated by aging, lead to irreversible declines in neural plasticity and resilience. In recent years, tetracyclines and their non-antibiotic derivatives have emerged as pharmacologically versatile molecules with strong potential for neuroprotection. Beyond their classical antibacterial effects, these compounds mitigate glial activation, suppress pro-inflammatory cytokine production, inhibit ferroptosis, and prevent protein aggregation, thereby targeting critical mechanisms underlying neurodegenerative progression. Despite these promising findings, it remains unclear how their molecular profiles interact with age-related changes in neuroimmune regulation, proteostasis, and metabolic homeostasis. Experimental and translational evidence indicates that tetracyclines such as minocycline and doxycycline can act on multiple targets relevant to both neuroinflammatory control and the prevention of pathological protein aggregation. Recent work also suggests that tetracycline derivatives chemically modified to abolish their antimicrobial activity may retain these neuroprotective properties while offering an improved safety profile for central nervous system applications. Their direct interactions with protein aggregation and phosphorylation—including amyloid-beta, alpha-synuclein, and tau—highlight a shared mechanism that may apply to a spectrum of age-related neurodegenerative conditions. However, key questions remain regarding how these compounds influence glial signalling in aged neural environments, penetrate the blood–brain barrier under compromised conditions, and can be optimized for long-term therapeutic use.This Research Topic aims to consolidate advances in understanding the neuroprotective, anti-inflammatory, and anti-aggregation mechanisms of tetracyclines and their derivatives. By integrating insights from pharmacology, neuroimmunology, and ageing neuroscience, it seeks to clarify how these pleiotropic agents can counteract the converging pathways that drive neuronal decline across the lifespan and in disease contexts. The goal is to stimulate cross-disciplinary dialogue that informs both the design of next-generation neuroprotective molecules and the development of precision therapeutic strategies for ageing populations.To gather further insights into the molecular and translational dimensions of tetracycline-based neuroprotection, we welcome articles addressing, but not limited to, the following themes:- Redesigning the tetracycline scaffold: from antibiotic chemistry to CNS therapeutics: Medicinal chemistry and structure–activity relationship (SAR) studies of tetracyclines and related compounds for central nervous system (CNS) applications. Topics include chemically modified tetracyclines, non-antibiotic derivatives, hybrid molecules, targeted conjugates, and strategies to optimise brain penetration, target selectivity, and therapeutic efficacy. Particular attention is encouraged to efforts that expand the tetracycline scaffold toward multitarget neuroprotection by integrating anti‑inflammatory, antioxidant, mitochondrial, and synaptic protective effects.- Reprogramming neurodegenerative pathways - mechanisms of neuroprotection: Molecular mechanisms underlying the neuroprotective actions of tetracycline‑based compounds, including modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, proteostasis, autophagy, lysosomal function, matrix metalloproteinases, iron homeostasis, and ferroptotic cell death. Studies addressing interactions with pathological protein aggregation—including conformational remodeling of misfolded protein assemblies into less toxic, less seeding‑competent, and less inflammogenic conformations of amyloid‑β, α‑synuclein, tau, and TDP‑43—and the regulation of cellular targets such as microglia and astrocytes are particularly encouraged.- Neuroimmune modulation of symptoms - tetracyclines in pain, dyskinesia, and glial dysfunction: Mechanisms by which tetracycline‑based compounds modulate neuroimmune and glial responses underlying neurological symptoms and disease complications. Topics include L‑DOPA‑induced dyskinesia, neuroinflammatory motor complications, neuropathic pain, pain‑related neuroimmune mechanisms, and the anti‑inflammatory and anti‑aggregation effects of tetracyclines in neuronal and glial systems. Studies that explore neuron–glia communication and the participation of complex cellular networks, including microglia, astrocytes, and NG2 glia (oligodendrocyte precursor cells), are particularly relevant.- From experimental models to translational readiness - preclinical evaluation of tetracyclines:Preclinical studies evaluating tetracycline‑based compounds in models of neurodegenerative diseases, including cellular systems, organoids, and animal models. Relevant topics include pharmacokinetics, pharmacodynamics, blood–brain barrier penetration, drug delivery and nanoformulation strategies, long‑term safety, formulation development, and preclinical efficacy in ageing and neurodegeneration. Mechanistic discoveries supporting disease‑modifying potential, including applications in Parkinson’s disease and L‑DOPA‑induced dyskinesia, are especially welcome.- Closing the translational gap - biomarker-guided clinical development:Clinical and translational studies of minocycline, doxycycline, chemically modified tetracyclines, and next‑generation derivatives for neurodegenerative diseases. Contributions addressing the translation of mechanistic insights into clinical benefit are encouraged, including optimized dosing regimens, timing of intervention, patient stratification, disease‑stage selection, functional outcome measures, biomarker-guided trial design, and critical reassessment of previous clinical trials aimed at achieving disease modification.We welcome Original Research, Review, Mini Review, Hypothesis and Theory, and Perspective articles. Topic editors: Rita Raisman-Vozari, Rosana Chehin, Elaine Del Bel Source: https://www.frontiersin.org/research-topics/82927/tetracyclines-and-their-non-antibiotic-derivatives-therapeutic-potential-in-neurodegeneration-and-neuronal-dysfunction