“Less is more”: A dose-response account of intranasal oxytocin pharmacodynamics in the human brain

Intranasal oxytocin is attracting attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating findings to humans has been hampered by remaining uncertainties about its pharmacodynamics and the methods used to probe its effects in the human brain. Using a dose-response design (9, 18 and 36 IU), we demonstrate that intranasal oxytocin-induced changes in local regional cerebral blood flow (rCBF) in the amygdala at rest, and in the covariance between rCBF in the amygdala and other key hubs of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects on local rCBF might vary by amygdala subdivision, highlighting the need to qualify dose-response curves within subregion. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to engage central targets. Finally, we demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity, which corroborates the validity of haemodynamic neuroimaging to probe the effects of intranasal oxytocin in the human brain. Data availability: Participants did not consent for open sharing of the data. Therefore, data can only be accessed from the corresponding author upon reasonable reques

FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates

The autophagy cargo receptor p62 facilitates the condensation of misfolded, ubiquitin-positive proteins and their degradation by autophagy, but the molecular mechanism of p62 signaling to the core autophagy machinery is unclear. Here, we show that disordered residues 326-380 of p62 directly interact with the C-terminal region (CTR) of FIP200. Crystal structure determination shows that the FIP200 CTR contains a dimeric globular domain that we designated the "Claw" for its shape. The interaction of p62 with FIP200 is mediated by a positively charged pocket in the Claw, enhanced by p62 phosphorylation, mutually exclusive with the binding of p62 to LC3B, and it promotes degradation of ubiquitinated cargo by autophagy. Furthermore, the recruitment of the FIP200 CTR slows the phase separation of ubiquitinated proteins by p62 in a reconstituted system. Our data provide the molecular basis for a crosstalk between cargo condensation and autophagosome formation

Pulsating aerosols for topical therapy of rhinosinusitis.

Rationale: There is a high incidence for nasal disorders including chronic sinusitis, but there is limited success in topical drug delivery to the nose and the paranasal cavities / sinuses. Most nasally administered aerosol drug formulations are efficiently filtered at the nasal valve and fail to reach the sinuses, which are virtually non-ventilated. Objectives: Pulsating airflows were applied and sinus ventilation was studied in a human nasal cast and in healthy human volunteers using dynamic 81mKr-gas gamma camera imaging. Furthermore, the efficiency of deposition and retention of 99mTc-DTPA radiolabelled aerosols during pulsating airflow inhalation was assessed. Results: In the nasal cast model ventilation efficiency of the sinuses was increased more than fivefold and aerosol deposition more than twentyfold compared to a delivery regime without pulsation. Up to 8% of the nebulized drug was deposited into the paranasal sinuses of the nasal cast model compared to only 0.2% without pulsation. Similarly during pulsating airflow efficient ventilation of the paranasal sinuses was confirmed in human healthy volunteers and this was associated with up to 5% sinus drug deposition. Surprisingly, clearance kinetics of the drug was reduced after pulsating airflow and associated with an up to twofold longer residence time of the drug at the site of deposition. Conclusions: Our data support the hypothesis that topical drug delivery in relevant quantities to the nose and osteomeatal areas, including paranasal sinuses, is possible using pulsating airflows. Furthermore, due to a delayed clearance, the frequency of drug applications can be reduced

Ventilation and drug delivery to the paranasal sinuses: Studies in a nasal cast using pulsating airflow.

Although there is a high incidence of nasal disorders including chronic sinusitis, there is limited success in the topical drug delivery to the nose and the paranasal sinuses. This is caused by the nose being an efficient filter for inhaled aerosol particles and the paranasal sinuses being virtually non ventilated. Method: The objective of this study was to visualize the efficiency of sinus ventilation in a nasal cast using dynamic 81mKr-gas imaging in combination with pulsating airflows. Furthermore, the efficiency of the deposition of radiolabelled aerosol was assessed. Results: Pulsation increased ventilation efficiency of the sinuses more than fivefold and aerosol deposition efficiency more than twentyfold, compared to delivery without pulsation. Furthermore pulsation increased aerosol deposition in the nasal airways by a factor of three. Using pulsating airflow Kr-gas ventilation and aerosol deposition efficiencies increased with increasing sinus volume. Pulsating airflow resulted in a deposition of up to 8% of the nebulized drug within the sinuses compared to 0.2% without pulsation. Conclusions: The study demonstrates the high efficiency of a pulsating airflow in paranasal sinus ventilation and aerosolized drug delivery. This proves that topical drug delivery to the paranasal sinuses in relevant quantities is possible