Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release

The ubiquitous volume-regulated anion channels (VRACs) facilitate cell volume control and contribute to many other physiological processes. Treatment with non-specific VRAC blockers or brain-specific deletion of the essential VRAC subunit LRRC8A is highly protective in rodent models of stroke. Here, we tested the widely accepted idea that the harmful effects of VRACs are mediated by release of the excitatory neurotransmitter glutamate. We produced conditional LRRC8A knockout either exclusively in astrocytes or in the majority of brain cells. Genetically modified mice were subjected to an experimental stroke (middle cerebral artery occlusion). The astrocytic LRRC8A knockout yielded no protection. Conversely, the brain-wide LRRC8A deletion strongly reduced cerebral infarction in both heterozygous (Het) and full KO mice. Yet, despite identical protection, Het mice had full swelling-activated glutamate release, whereas KO animals showed its virtual absence. These findings suggest that LRRC8A contributes to ischemic brain injury via a mechanism other than VRAC-mediated glutamate release

Short Communication Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

Number of references: 28 Number of words in Abstract: 240 Number of words in Introduction: 49

Novel Qualitative Structure-Activity Relationships for the Antinociceptive Actions of H 2 Antagonists, H 3 Antagonists and Derivatives 1

ABSTRACT Recent studies have shown that cimetidine, burimamide and improgan (also known as SKF92374, a cimetidine congener lacking H 2 antagonist activity) induce antinociception after intracerebroventricular administration in rodents. Because these substances closely resemble the structure of histamine (a known mediator of some endogenous analgesic responses), yet no role for known histamine receptors has been found in the analgesic actions of these agents, the structure-activity relationships for the antinociceptive effects of 21 compounds chemically related to H 2 and H 3 antagonists were investigated in this study. Antinociceptive activity was assessed on the hot-plate and tail-flick tests after intracerebroventricular administration in rats. Eleven compounds induced time-dependent (10-min peak) and dose-dependent antinociceptive activity with no observable behavioral impairment. ED 50 values, estimated by nonlinear regression, were highly correlated across nociceptive assays (r 2 ϭ 0.98, n ϭ 11). Antinociceptive potencies varied more than 6-fold (80 -464 nmol), but were not correlated with activity on H 1 , H 2 or H 3 receptors. Although highly potent H 3 antagonists such as thioperamide lacked antinociceptive activity, homologs of burimamide and thioperamide containing N-aromatic substituents retained H 3 antagonist activity and also showed potent, effective analgesia. A literature review of the pharmacology of these agents did not find a basis for their antinociceptive effects. Taken with previous findings, the present results suggest: 1) these compounds act on the brain to activate powerful analgesic responses that are independent of known histamine receptors, 2) the structure-activity profile of these agents is novel and 3) brain-penetrating derivatives of these compounds could be clinically useful analgesics

Antinociceptive activity of furan-containing congeners of improgan and ranitidine

Furan-containing congeners of the histamine H(2) receptor antagonist ranitidine were synthesized and tested for improgan-like antinociceptive activity. The most potent ligand of the series, VUF5498, is the most potent improgan-like agent described to date (ED(50)= 25 nmol, icv). This compound is approximately equal in potency with morphine. These non-imidazole, improgan-like pain relievers further define the structural requirements for analgesics of this class and are important tools for ongoing mechanism-based studies

Significance of GABAergic systems in the action of improgan, a non-opioid analgesic

Improgan is the prototype drug from a new class of non-opioid analgesics chemically related to histamine and histamine antagonists, but the mechanism of action of these compounds has not been identified. Because several classes of analgesics act in the brain by reducing GABAergic inhibition of endogenous pain-relieving circuits, and because the activity of these substances is abolished by the GAB

Seismic reflection study of the geologic structure underlying southern Narragansett Bay, Rhode Island

A subbottom reflection survey of southern Narragansett Bay, Rhode Island was made by means of a continuous seismic reflection technique (the Continuous Seismic Profiler)developed at the Woods Hole Oceanographic Institution (Knott and Hersey, 1956). The observational program was conducted in May, 1958 under contract with the Corps of Engineers, U. S. Army, and in May, 1960 under contract with the Bureau of Ships, U . S. Navy, to obtain foundation data for locating hurricane barriers (Corps of Engineers, 1957) and to develop techniques for studying the geologic structure of shallow water areas. At the Woods Hole Oceanographic Institution this work is part of a continuing, broader program directed toward describing the structures and tracing the geologic history of continental margins. The Continuous Seismic Profiler employs a wide-band sound source the pulses from which are reflected from the bottom and from sediment and rock layers beneath the bottom. The sound pulse is synchronized with the sweep of a Precision Graphic Recorder (PGR), which records sound energy received at an underwater detector. (In 1958 the sound source was an early form of the Sparker, while in 1960 the Edgerton Thumper was the source. (These instruments are described below.) When the sound source and the detector are towed from a boat, the reflected sound energy is recorded to present a continuously correlated picture of subbottom structure. Measurements in Narragansett Bay were made south of the Jamestown Bridge in the West Passage and between Conanicut Island and Newport Neck in the East Passage (Fig . 1A and lB). Two additional traverses were made across the bay in areas to the north where core data are available (Fig. 2).The Bureau of Ships under Contract NObsr 72521 and the U. S. Army Corps of Engineers under Contract DA-19-016 CIVENG-58-6

Absence of 5-HT3 and cholinergic mechanisms in improgan antinociception

Improgan, an analgesic derived from histamine antagonists, acts in the brain stem to activate descending non-opioid, pain-relieving circuits, but the mechanism of action of this drug remains elusive. Because improgan has a moderate affinity for 5-H

Improgan-like analgesics: A family of compounds derived from histamine antagonists

The antinociceptive activity of some centrally-administered