Biology subjects

Reznikov, L. R.

Publications and source records attributed to Reznikov, L. R..

5 recordsLinked to original sources

bioRxiv2025

Divergent Neurobehavioral Effects of CFTR Modulators Elexacaftor and Ivacaftor in Mice

Recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination therapies have markedly improved survival and quality of life for people with cystic fibrosis (CF). Among these, the elexacaftor-tezacaftor-ivacaftor combination (Trikafta) and its updated formulation, vanzacaftor-tezacaftor-deutivacaftor (Alyftrek), represent major therapeutic milestones. However, emerging reports suggest that Trikafta may contribute to anxiety and depression in some people with CF. In this study, we investigated the neurobehavioral effects of elexacaftor and ivacaftor in mice. Acute administration of elexacaftor elicited anxiety-like behavior, while ivacaftor induced depressive-like behavior. Additionally, we confirmed the presence of Cftr mRNA in the amygdala and hippocampus, brain regions implicated in anxiety and depression. These findings provide preclinical support for the reported mental health side effects experienced by some people with CF and offer new insights into CFTR function within the central nervous system, potentially guiding the development of future CF therapies with improved neuropsychiatric profiles.

physiology↗

bioRxiv2020

Durable Changes to Airway Mucus and Fluid Secretion Following Cholinergic Challenge

PurposeMucus abnormalities are central to the pathophysiology of several chronic airway diseases. Mucus secretion and clearance are regulated, in part, by cholinergic innervation. Prolonged cholinergic stimulation may contribute to mucus abnormalities in disease. Thus, we tested the hypothesis that prolonged cholinergic stimulation gives rise to lasting mucus abnormalities in airways. MethodsWe delivered aerosolized bethanechol, a cholinergic agonist, to pig airways. Forty-eight hours later, we measured mucus secretion and mucociliary transport in tracheal segments ex vivo. Tracheal and bronchoalveolar lavage concentrations of the major secreted mucus glycoproteins, mucin5B (MUC5B) or mucin5AC (MUC5AC), were measured with ELISA and antibody labeling. Pig airway epithelia were cultured at the air-liquid interface and treated with bethanechol for forty-eight hours. Stimulated fluid secretion was measured with reflected microscopy and Ussing chambers were used to measure ion transport. ResultsAirways from bethanechol-challenged pigs exhibited sheet-like mucus films, which were not associated with a greater abundance of MUC5AC or MUC5B. Epithelia treated with bethanechol had diminished fluid secretion and decreased Cl- transport. However, mucus and fluid alterations were not associated with impaired mucociliary transport. ConclusionsThese data suggest that cholinergic transmission induces sustained alterations in airway mucus properties. Such defects might compound and/or contribute to persistent mucus phenotypes found after the resolution of airway inflammation.

physiology↗

bioRxiv2019

Long-term culturing of porcine nodose ganglia

BackgroundNeuronal cell cultures are widely used in the field of neuroscience. Cell dissociation allows for the isolation of a desired cell type, yet the complexity that distinguishes the nervous system is often lost as a result. Thus, culturing neural tissues in ex vivo format provides a physiological context that more closely resembles the in vivo environment. Nodose ganglia neurons have been extensively studied both in dissociated form and acutely in slice format. However, methods to culture long-term ex vivo have not been established.\n\nNew MethodWe developed a simple method to culture nodose ganglia neurons from neonatal pigs long-term in ex vivo format using an in-house media formulation derived from commercially available components.\n\nResultsCultures were viable for approximately 12 months. mRNA expression for nestin, a marker of neural progenitor cells, was stable across time. Vasoactive intestinal peptide and tachykinin, markers of nodose neurons, showed either no statistically significant differences or decreased across time, respectively. mRNA expression for glia fibrillary acidic protein and myelin basic protein showed no statistically significant differences over time.\n\nComparison with Existing Method(s)There are currently no methods that describe long-term culturing of porcine nodose ganglia. Further, the media formulation we developed is new and not previously reported.\n\nConclusionsThe simple procedure we developed for culturing nodose ganglia will enable both short-term and long-term investigations aimed at understanding peripheral ganglia in vitro. It is also possible that the methods described herein can be applied to other animal models, adult samples, and other neural tissues.

neuroscience↗

bioRxiv2019

Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of cystic fibrosis (CF). Although airway acidification occurs early in CF, whether transient acidification is sufficient to initiate mucus abnormalities is unknown. We studied mucus secretion and mucus transport in piglets forty-eight hours following an intra-airway acid challenge. Acid-challenged piglet airways were distinguished by increased mucin 5B (MUC5B) in the submucosal gland but decreased lung lavage fluid MUC5B, following in vivo cholinergic stimulation, suggesting a failure in submucosal gland secretion. Concomitantly, intrapulmonary airways were obstructed with glycoprotein rich material under both basal and methacholine-stimulated conditions. To mimic a CF-like environment, we also studied mucus secretion and transport under diminished bicarbonate and chloride transport conditions ex vivo. Cholinergic stimulation in acid-challenged piglet airways induced extensive mucus films, greater mucus strand formation, increased dilation of submucosal gland duct openings and decreased mucociliary transport. Finally, to elucidate potential mediators of acid-induced mucus defects, we investigated diminazene aceturate, a small molecule that inhibits the acid-sensing ion channel (ASIC). Diminazene aceturate restored surface MUC5B in acid-challenged piglet airways under basal conditions, mitigated acid-induced airway obstruction, and magnified the number of dilated submucosal gland duct openings. These findings suggest that even transient airway acidification early in life might have profound impacts on mucus secretion and transport properties. Further they highlight diminazene aceturate as an agent that might be beneficial in alleviating certain mucus defects in CF airway disease.\n\nOne sentence summaryEarly life airway acidification has profound impacts on mucus secretion and transport.

physiology↗

bioRxiv2019

Attenuated amiloride-sensitive current and augmented calcium-activated chloride current in marsh rice rat (Oryzomys palustris) airways

Prolonged heat and sea salt aerosols pose a challenge for the mammalian airway, placing the protective airway surface liquid (ASL) at risk for desiccation. Thus, mammals inhabiting salt marshes might have acquired adaptations for ASL regulation. We studied the airways of the rice rat, a rodent that inhabits salt marshes. We discovered negligible Na+ transport through the epithelial sodium channel (ENaC). In contrast, carbachol induced a large Cl- secretory current that was blocked by the calcium-activated chloride channel (CaCC) inhibitor CaCCinh-A01. Decreased mRNA expression of , {beta}, and {gamma} ENaC, and increased mRNA expression of the CaCC transmembrane member 16A distinguished the rice rat airway. Rice rat airway cultures also secreted fluid in response to carbachol and displayed an exaggerated expansion of the ASL volume when challenged with 3.5% NaCl. These data suggest that the rice rat airway might possess unique ion transport adaptations to facilitate survival in the salt marsh environment.

physiology↗