In this study, we characterized PAC-832, a small-molecule GalR1 antagonist with sub-micromolar potency (IC₅₀ = 0.28 μM), 30-fold selectivity over GalR2 and GalR3, and excellent brain penetration and drug-like properties. In functional cell-based assays, PAC-832 reversed galanin-mediated suppression of acetylcholine release. In a scopolamine challenge model, PAC-832 attenuated cognitive deficits in the Y-maze and NOR tasks, with effect sizes comparable to donepezil.

The scopolamine model is widely used in behavioral mouse research to evaluate compounds for procognitive activity. However, because scopolamine impairs cognition by blocking muscarinic receptors rather than by reducing acetylcholine release, our behavioral results do not directly assess whether PAC-832 acts by restoring cholinergic signaling in vivo, or whether it acts through an alternative downstream mechanism. Establishing the former will require direct measurement of acetylcholine release in the CNS (e.g. using microdialysis or biosensor-based approaches) and/or GalR1-dependent in vivo validation (e.g. using transgenic GalR1-knockout mice).

Nonetheless, our work addresses a longstanding pharmacological gap in the galanin field. Despite decades of work implicating galanin signaling in CNS function and disease, translational progress has been limited by a lack of subtype-selective, brain-penetrant small molecule galanin modulators. Recent therapeutic development within the galanin field has largely focused on GalR2 agonism, while GalR1-targeting approaches have remained dependent on peptide tools unable to pass the blood-brain barrier. PAC-832 is, to our knowledge, the first GalR1-selective small molecule antagonist with sufficient brain exposure to test the effects of GalR1 antagonism following peripheral administration.

Intraoperative functional brain mapping is an essential and intricate technique in modern-day glioma surgery. This article is not a review of the literature but of the technical protocol at our institution that has evolved over the recent decades to the current time and is intended to highlight details that enable us to perform maximal safe resection of gliomas.

Prior to surgery, anatomical and functional imaging protocols are obtained to determine the tumor to be resected within its anatomical and functional environment. Preoperative assessments are used to determine which mapping procedures and tasks are most appropriate. Cortical and subcortical motor and language mapping using low and high frequency stimulation paradigms are applied when appropriate during resection. Methods to interpret findings and troubleshoot issues are reviewed herein.

All preoperative imaging including magnetic resonance imaging, magnetoencephalography of functional cortex, and diffusion tensor imaging of subcortical tracts are uploaded into the neuronavigation station and used throughout surgery for guidance. The decision to continue with tumor resection is based on constant feedback from the mapping paradigms as functional pathways are approached in real time. Both awake and asleep anesthesia regimens are utilized depending on the type of testing required to assess and preserve functional areas during tumor resection. Postoperatively, deficits are assessed using MRI along with clinical exam to predict whether they will be temporary or permanent.

Alzheimer’s disease is driven by a buildup of a toxic protein called Tau that kills neurons. As toxic Tau spreads to new regions of the brain, symptoms worsen and ultimately become fatal.

Now, researchers have discovered that, in mice, a brain protein called Arc helps spread Tau from sick brain cells to healthy ones.

If therapies could be designed to target the spread, they could be a powerful tool to stop Alzheimer’s disease from getting worse.