Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington's Disease: Data from the TRACK and ENROLL HD Cohorts.

Background: There is evidence for dysregulated cholesterol homeostasis in Huntington's disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD.

The core spindle pole body scaffold Ppc89 links the pericentrin orthologue Pcp1 to the fission yeast spindle pole body via an evolutionarily conserved interface.

Centrosomes and spindle pole bodies (SPBs) are important for mitotic spindle formation and serve as cellular signaling platforms. Although centrosomes and SPBs differ in morphology, many mechanistic insights into centrosome function have been gleaned from SPB studies. In the fission yeast , the α-helical protein Ppc89, identified based on its interaction with the septation initiation network scaffold Sid4, comprises the SPB core.

ST-2560, a selective inhibitor of the Na1.7 sodium channel, affects nocifensive and cardiovascular reflexes in non-human primates.

Background And Purpose: The voltage-gated sodium channel isoform Na1.7 is a high-interest target for the development of non-opioid analgesics due to its preferential expression in pain-sensing neurons. Na1.

Pharmacological characterization of SAGE-718, a novel positive allosteric modulator of N-methyl-d-aspartate receptors.

Background And Purpose: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction.

Experimental Approach: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile.

Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions.

N-methyl-D-aspartate receptors (NMDARs) play vital roles in normal brain functions (i.e., learning, memory, and neuronal development) and various neuropathological conditions, such as epilepsy, autism, Parkinson's disease, Alzheimer's disease, and traumatic brain injury.