Therapeutic Potential of Neuroactive Steroids and SerpinA3n in Asthma and Neurological Conditions

Ehab Ghoneim^*
*Correspondence: Ehab Ghoneim, Department of Molecular Neuroscience and Steroid Biochemistry, Cairo University, Cairo, Egypt, Email:

Introduction

The complexity of neurological and respiratory disorders, such as epilepsy, depression and asthma, demands innovative therapeutic strategies that target underlying molecular pathways to improve patient outcomes. Neuroactive steroids, a class of endogenous or synthetic compounds that modulate brain function, have gained attention for their neuroprotective, anti-inflammatory and neuromodulatory properties, offering potential treatments for neurological and psychiatric conditions. These steroids influence neurotransmitter systems, such as GABA and glutamate and regulate stress responses, making them promising candidates for disorders characterized by neural dysregulation. Similarly, in the context of respiratory diseases, SerpinA3n, a serine protease inhibitor, has emerged as a key regulator of inflammation and tissue remodeling in asthma, particularly in pediatric models. Research using neonatal mouse models of Ovalbumin (OVA)-induced asthma has shown that SerpinA3n modulates airway hyper-reactivity and collagen deposition, highlighting its therapeutic relevance. The convergence of these findings underscores the potential of neuroactive steroids and SerpinA3n as targeted therapies, addressing distinct yet overlapping challenges in neurological and respiratory health through precision medicine approaches [1].

Description

Neuroactive steroids exert their therapeutic effects by interacting with neurotransmitter receptors and modulating neuronal excitability, neuroinflammation and neuroplasticity. These compounds, including allopregnanolone and DeHydroEpi Androsterone (DHEA), enhance GABAergic inhibition or attenuate glutamatergic excitation, stabilizing neural networks disrupted in conditions like epilepsy, anxiety and depression. For instance, allopregnanolone, a progesterone metabolite, has shown efficacy in reducing seizure frequency in epilepsy models by potentiating GABA-A receptor activity. Beyond seizure control, neuroactive steroids exhibit neuroprotective properties, mitigating neuronal damage in traumatic brain injury and neurodegenerative diseases like Alzheimerâ??s by reducing oxidative stress and inflammation. Their ability to modulate the Hypothalamic-Pituitary-Adrenal (HPA) axis also makes them effective in managing stress-related disorders, such as Post-Traumatic Stress Disorder (PTSD). Clinical trials have explored synthetic neuroactive steroids, like brexanolone, for postpartum depression, demonstrating rapid symptom relief with minimal side effects. However, challenges remain, including optimizing delivery methods to cross the blood-brain barrier and minimizing off-target effects. Advances in neurosteroid analogs and nanoparticle-based delivery systems are addressing these issues, enhancing their therapeutic potential. The versatility of neuroactive steroids lies in their broad applicability, offering a unifying approach to treating diverse neurological and psychiatric conditions through targeted modulation of brain function.

In parallel, SerpinA3n has shown significant promise in managing asthma, particularly in neonatal models where early-life interventions are critical to prevent chronic disease progression. Asthma, characterized by airway inflammation, hyper-reactivity and remodeling, is driven by immune responses to allergens like ovalbumin. Studies in neonatal mice demonstrate that SerpinA3n knockout reduces airway hyper-reactivity, inflammatory cell infiltration and collagen deposition in lung tissues, key features of asthma pathology. These effects are reversed by administering recombinant SerpinA3n, confirming its regulatory role in asthma. SerpinA3n inhibits proteases like neutrophil elastase, which contribute to tissue damage and inflammation, thereby attenuating airway remodeling and mucus hypersecretion. This mechanism suggests that SerpinA3n could serve as a therapeutic target to dampen exaggerated immune responses in allergic asthma. Unlike corticosteroids, which broadly suppress immunity and carry side effects, SerpinA3n offers a more targeted approach, potentially reducing long-term complications in pediatric patients. Challenges include translating these findings to humans, as mouse models may not fully recapitulate human asthma and developing delivery methods, such as inhalable formulations, to target lung tissues effectively. Ongoing research into SerpinA3n agonists or gene therapies could unlock its full therapeutic potential, particularly for early intervention in at-risk populations [2].

Conclusion

The therapeutic potential of neuroactive steroids and SerpinA3n represents a significant advancement in addressing neurological and respiratory disorders. Neuroactive steroids offer a versatile approach to treating conditions like epilepsy, depression and neurodegenerative diseases by modulating brain function, reducing inflammation and promoting neuroprotection. Concurrently, SerpinA3nâ??s role in attenuating airway inflammation and remodeling in neonatal asthma models highlights its promise as a targeted therapy for pediatric respiratory diseases. Together, these findings pave the way for precision medicine, leveraging molecular insights to develop safer, more effective treatments. As research progresses, overcoming challenges like delivery optimization and clinical translation will be crucial to realizing the full impact of these therapies, improving quality of life for patients with complex neurological and respiratory conditions.

Acknowledgement

None.

Conflict of Interest

None.

References

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2. Zhang, Hoi-Tao, Ping Wang, Yuan Li and Yong-Bo Bao. "SerpinA3n affects ovalbumin (OVA)-induced asthma in neonatal mice via the regulation of collagen deposition and inflammatory response." Respir Physiol Neurobiol 288 (2021): 103642.

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