Our previous studies have demonstrated toxicity in spinal cord neuronal systems of middle-aged rats with continuous intrathecal infusion of N-methyl-D-aspartate (NMDA). The present study was undertaken to determine when during the course of excitotoxicity vascular changes occur. The model used was intrathecal infusion of NMDA in the region of the lumbar enlargement of the spinal cord. Horseradish peroxidase (HRP) was used as a marker of vascular permeability alterations occurring in this model. Pathological changes were observed in the cord gray matter of all rats infused with 30-60 micrograms/min NMDA for 30 or 60 min. The changes consisted of swelling of dendrites which gave the neuropil a vacuolated appearance. There was expansion of the extracellular spaces in these areas and neurons were shrunken with pyknotic nuclei. These changes were more frequently encountered in the posterior than anterior horns and were specific for NMDA since they did not occur in NMDA-infused rats pretreated with MK-801, a specific NMDA antagonist. Endothelial dysfunction manifested as increased permeability to HRP. This was a consistent finding in all rats infused with the higher dose of NMDA and was less frequent in those infused with 30 micrograms/min and no vascular changes were observed in rats infused with NMDA for 30 min despite the presence of tissue changes. Increased permeability affected all types of vessels but principally, capillaries and venules. There was no evidence of endothelial necrosis or vascular occlusion. This study demonstrates that in excitotoxin-mediated tissue damage, breakdown of the blood-brain barrier follows the development of nervous tissue damage. Thus, edema is not a significant feature of early lesions in excitotoxin-induced brain injury.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by left ventricular hypertrophy, hyperdynamic contraction, and impaired relaxation of the heart. These functional derangements arise directly from altered sarcomeric function due to either mutations in genes encoding sarcomere proteins, or other defects such as abnormal energetics. Current treatment options do not directly address this causal biology but focus on surgical and extra-sarcomeric (sarcolemmal) pharmacological symptomatic relief. Mavacamten (formerly known as MYK-461), is a small molecule designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin, the fundamental motor of the sarcomere. This review summarizes the mechanism and translational progress of mavacamten from proteins to patients, describing how the mechanism of action and pharmacological characteristics, involving both systolic and diastolic effects, can directly target pathophysiological derangements within the cardiac sarcomere to improve cardiac structure and function in HCM. Mavacamten was approved by the Food and Drug Administration in April 2022 for the treatment of obstructive HCM and now goes by the commercial name of Camzyos. Full information about the risks, limitations, and side effects can be found at www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf .

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Continuous intrathecal infusion of N-methyl-D-aspartate (NMDA) at the level of the lumbar enlargement of the spinal cord in middle-aged rats produced dose-dependent toxicity of spinal cord neuronal systems. Toxicity was enhanced by coadministration of glycine, but was significantly reduced when NMDA was co-administered with the competitive inhibitor DL-2-amino-5-phosphovaleric acid or the noncompetitive inhibitor MgSO4. The toxic effects of NMDA were manifest most dramatically and at the lowest concentrations in the neuropil, while neuronal loss was obvious at higher concentrations. The distribution and intensity of reactive astrocytosis was consistent with the known regional and subcellular distribution of NMDA receptors in the spinal cord of rats. The increase in ribosomes and rough endoplasmic reticulum observed in anterior horn cells suggested an increase of cell metabolism reflecting either a nonspecific response to injury or a specific increase in cell metabolism secondary to sustained activation of NMDA receptors. The present studies implicate excitatory amino acid receptors of the NMDA type in producing toxicity to selected neuronal populations of the spinal cord. This model provides a system for studies of the protective effects and rescue of neuronal populations susceptible to the toxic effects of excitatory amino acids.