Biology subjects

Airan, R. D.

Publications and source records attributed to Airan, R. D..

6 recordsLinked to original sources

bioRxiv2026

Ibogaine is associated with reorganization of high-beta brain networks in veterans with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a debilitating condition that affects millions of veterans. A recent observational study in 30 veterans showed that a single dose of the atypical psychedelic ibogaine can be highly effective at treating PTSD up to twelve months later. Although a prior study demonstrated that ibogaine transiently alters electroencephalography (EEG) power in various frequency bands, the long-term, network-level neural mechanisms targeted by ibogaine are unclear. Here, we investigated whether ibogaine-related clinical improvements are associated with the reorganization of certain brain networks. We applied a novel framework, FREQuency-resolved brain Network Estimation via Source Separation (FREQ-NESS), to identify frequency-specific brain networks in resting-state EEG data acquired at baseline, three to four days after treatment (immediate-post), and one month after ibogaine. At both the immediate-post and one month-post timepoints, high-beta (24 and 25 Hz) networks shifted away from frontal areas and towards posterior regions, an effect that was replicated in an independent EEG dataset on ibogaine treatment for opioid use disorder. This posterior shift was significantly correlated with improvements in PTSD symptoms at both timepoints. Neural field modeling demonstrated that these posterior high-beta shifts are associated with increases in corticocortical, but not corticothalamic, connectivity. Our results are consistent with prior evidence implicating aberrant frontal beta-band activity in PTSD. Overall, we demonstrate that the reconfiguration of high-beta brain networks could be a robust biomarker for ibogaines therapeutic effects.

neuroscience↗

bioRxiv2025

Ethological profiling of pain and analgesia in a mouse model of complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a form of chronic post-injury pain affecting the extremities. The mouse tibial fracture- cast model was developed to enable preclinical study of CRPS mechanisms and guide condition-specific drug development. Given the inherent limitations of reflex pain measures in mice, we sought to characterize pain-like behaviors in this model more holistically. We evaluated spontaneous and evoked pain and naturalistic behaviors after tibial fracture-cast injury in male mice in neutral and aversive environments using LabGym. Here, we report a unique ethological signature of pain in injured mice characterized by reflexive allodynia, thermal hyperalgesia, frequent grooming and reduced rearing in neutral and aversive environments, and decreased paw withdrawal and increased paw licking in an aversive environment. As proof-of-concept, we also leveraged this holistic behavioral evaluation for drug screening by characterizing the peripheral versus central effects of targeting alpha-2 receptors (2-AR) in the tibial fracture-cast model. We evaluated the impact of systemic delivery of dexmedetomidine (DEX), a selective 2-AR agonist, with or without antagonists, on holistic behavioral metrics in injured male mice. We found that DEX reduced mechanical allodynia primarily via central 2-ARs. DEX also decreased motion metrics, grooming and rearing in an open field, and distinctly affected the quality and quantity of grooming in an aversive environment, and this effect was not suppressed by systemic 2-AR antagonists. Ultimately, this study holistically captures pain-related behaviors and provides a detailed characterization of the relative contributions of peripheral and central 2-ARs to alpha2-mediated analgesia in male mice after tibial fracture-cast injury.

neuroscience↗

bioRxiv2023

Acoustomechanically activatable liposomes for ultrasonic drug uncaging

Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest. One Sentence SummaryIncorporating a few percent sucrose into a liposome transforms it into an immediately translatable vehicle for noninvasive, on-demand ultrasound-targeted drug delivery.

bioengineering↗

bioRxiv2022

Sex dependence of opioid-mediated responses to subanesthetic ketamine

Subanesthetic ketamine rapidly and robustly reduces depressive symptoms in patients with treatment-resistant depression. While it is commonly classified as an N-methyl D-aspartate receptor (NMDAR) antagonist, our picture of ketamines mechanistic underpinnings is incomplete. Recent clinical evidence has indicated, controversially, that a component of the efficacy of ketamine in depression may be opioid dependent. Using pharmacological functional ultrasound imaging in rats, we found that blocking opioid receptors suppressed neurophysiologic changes evoked by ketamine, but not by a more selective NMDAR antagonist, in regions implicated in the pathophysiology of depression and in reward processing. Importantly, this opioid-dependent response was strongly sex dependent, as it was not evident in female subjects and was fully reversed by surgical removal of the male gonads. We observed similar opioid-mediated sex-dependent effects in ketamine-evoked structural plasticity and behavioral sensitization. Together, these results underscore the potential for ketamine to induce its affective responses via opioid signaling, and indicate that this opioid dependence may be strongly influenced by subject sex. These factors should be more directly assessed in future clinical trials. One-Sentence SummarySubanesthetic ketamine evokes opioid-mediated behavioral and neurophysiological effects in male, but not female, rats.

neuroscience↗

bioRxiv2020

Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

Intrathecal drug delivery is routinely used to bypass the blood-brain barrier in treating varied central nervous system conditions. However, the utility of intrathecal delivery is limited by poor parenchymal uptake of agents from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol significantly increases the brain parenchymal uptake of intrathecally administered drugs and antibodies. Essentially, we show that our protocol of transcranial ultrasound can accelerate glymphatic fluid transport from the cisternal space into the parenchymal compartment. Specifically, we administered small ([~]1kDa) and large ([~]150 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using both real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of each agent into the brain parenchyma from the cisternal cerebrospinal fluid, notably with no brain parenchymal damage. The low intensity of the ultrasound and its noninvasiveness underscores the ready path to clinical translation of this technique for whole-brain delivery of a variety of agents. Furthermore, this technique can be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated. eTOC SummaryA translation-ready ultrasound technique enhances the brain penetration of intrathecally delivered agents via upregulating the glymphatic pathway.

bioengineering↗

bioRxiv2018

Polymeric perfluoropentane nanoemulsions are a versatile platform for ultrasonic drug uncaging

Catheter-based intra-arterial drug therapies have proven effective for a range of oncologic, neurologic, and cardiovascular applications. However, these procedures are limited by their invasiveness, as well as the relatively broad drug spatial distribution that is achievable with selective arterial catheterization. The ideal technique for local pharmacotherapy would be noninvasive and would flexibly deliver a given drug to any region of the body. Combining polymeric perfluorocarbon nanoemulsions with existent clinical focused ultrasound systems could in principle enable noninvasive targeted drug delivery, but it has not been clear whether these nanoparticles could provide the necessary drug loading, stability, and generalizability across a range of drugs to meet these needs, beyond a few niche applications. Here, we directly address all of those challenges and fully develop polymeric perfluorocarbon nanoemulsions into a generalized platform for ultrasound-targeted drug delivery with high potential for clinical translation. We demonstrate that a wide variety of drugs may be effectively uncaged with ultrasound using these nanoparticles, with drug loading increasing with hydrophobicity. We also set the stage for clinical translation by delineating production protocols that hew to clinical standards and yield stable and optimized ultrasound-activated drug-loaded nanoemulsions. Finally, as a new potential clinical application for these nanoemulsions, we exhibit their in vivo efficacy and performance for cardiovascular applications, by achieving local vasodilation in the highest flow vessel of the body, the aorta. This work establishes the power of polymeric perfluorocarbon nanoemulsions as a clinically-translatable platform for effective noninvasive ultrasonic drug uncaging for myriad targets in the brain and body.

bioengineering↗