Biology subjects

Audu, D.

Publications and source records attributed to Audu, D..

3 recordsLinked to original sources

bioRxiv2026

Therapeutic Potential of Melatonin, Erythropoietin, and TRPV4 Antagonism in a Preclinical Model of Genetic Hydrocephalus

Symptomatic hydrocephalus is a neuropathological disorder of cerebrospinal fluid (CSF) homeostasis characterized by abnormal accumulation of CSF and progressive ventricular enlargement. Current treatment relies primarily on surgical CSF diversion, which is invasive and associated with substantial rates of treatment failure and surgical revisions. Congenital hydrocephalus can be caused by genetic pathologies; for example, a point mutation in the Meckel-Gruber type 3, Tmem67, gene produces a congenital hydrocephalus phenotype in rats, characterized by progressive ventriculomegaly. Here, we evaluated a combinatorial cocktail therapeutic strategy consisting of erythropoietin (EPO), melatonin (MLT), and the transient receptor potential vanilloid 4 (TRPV4) antagonist, RN1734 (RN), in the Tmem67-- rat model of congenital hydrocephalus. Magnetic Resonance Imaging (MRI) demonstrated marked progression of ventriculomegaly in untreated Tmem67-- rats between postnatal (P) 7 and P15. RN1734 and EPO+MLT+RN1734 (triple therapy) from P7-P14 prevented further ventricular expansion. Hydrocephalus is associated with structural disruption of the periventricular white matter (WM) and ependymal lining (EL), accompanied by regionally increased TLR4 and NLRP3-associated inflammatory signaling. EPO+MLT, RN1734, or triple therapy differentially attenuated these inflammatory responses. The triple combination reduced both TLR4 and NLRP3 protein abundance within the affected periventricular region and ameliorated the structural alterations. These findings support a combined therapeutic approach that addresses ventricular pathology, inflammation and periventricular structural consequences of congenital hydrocephalus.

neuroscience↗

bioRxiv2026

Use of Integrative Proteomic Analysis to Uncover Shared Molecular Signatures Across Distinct Forms of Hydrocephalus

Hydrocephalus is a heterogeneous disease characterized by disruption of cerebrospinal fluid (CSF) dynamics and can arise from diverse etiologies, including post-hemorrhagic hydrocephalus (PHH), hydrocephalus following subarachnoid hemorrhage (SAH), post-infectious hydrocephalus (PIH), and idiopathic normal pressure hydrocephalus (iNPH). Hydrocephalus has high disease burden in pediatric and older populations and a marked increase in prevalence with advancing age. Despite this high incidence, the underpinning molecular and signaling pathway alterations remain incompletely understood. Hence CSF proteomic profiling would enable a robust and high-resolution approach for exploring disease-specific biomarkers and to discover shared molecular mechanisms underlying hydrocephalus. In this study, we performed a cross-study proteomic analysis to evaluate biomarker proteins reported across PHH, SAH, PIH, and iNPH groups. Using published proteomic datasets, we comparatively analyzed CSF proteins to investigate the differentially expressed proteins (DEPs), their common molecular signatures, and enriched biological pathways across hydrocephalus groups. Across etiologies, recurrently altered proteins were predominantly associated with inflammatory signaling (cytokine, chemokine, interleukin-(IL-17), tumor necrosis factor (TNF)), toll-like receptor (TLR) signaling, blood-brain-barrier (BBB) disruption leading to coagulation cascades, and neuronal injury responses. Hemorrhage-associated forms of hydrocephalus (PHH and SAH) demonstrated enriched coagulation and hemoglobin-related pathways, whereas infection associated forms (PIH) showed enhanced immune and inflammatory responses. iNPH exhibited alterations in proteins linked to neurodegeneration, synaptic function, and impaired CSF clearance. Interestingly, our cross-study analyses identified recurrently dysregulated proteins across hydrocephalus subtypes. Collectively, our cross-study proteomic analyses define shared and etiology-specific proteomic signatures across hydrocephalus subtypes and identify potential CSF-based biomarkers for diagnostic stratification and future precision therapeutic approaches.

neuroscience↗

bioRxiv2026

TRPV4 antagonist efficacy in a post-hemorrhagic hydrocephalus pig model

Hydrocephalus occurs across the age spectrum but is particularly prevalent in young and old individuals. One form of this disease is post-hemorrhagic hydrocephalus (PHH), which is a life-threatening sequela of intraventricular hemorrhage (IVH). There are no effective non-surgical interventions for the treatment of PHH or other forms of hydrocephalus. Progress has been limited by the lack of gyrencephalic animal models that exhibit high fidelity to human conditions. Here, we establish a pathophysiologically relevant novel swine model of IVH that recapitulates key features of severe PHH, including sustained ventriculomegaly, elevated intracranial pressure (ICP), neuroinflammation and white matter injury. Using this model, we test the therapeutic potential of pharmacologic inhibition of the transient receptor potential vanilloid 4 (TRPV4) non-specific cationic channel. The orally bioavailable TRPV4 antagonist GSK2789917 penetrates the blood-brain barrier, and prevents progression to PHH when administered 2 days after IVH. Specifically, GSK2789917 prevents the development of ventriculomegaly, suppresses early ICP elevations and prevents or reverses inflammasome activation. These findings establish a clinically relevant large-animal model of PHH and identify TRPV4 antagonism as a promising treatment for hydrocephalus.

neuroscience↗