Interleukin-1ß in Central Nervous System Injury and Repair.

Acute inflammation is a self-limiting, complex biological response mounted to combat pathogen invasion, to protect against tissue damage, and to promote tissue repair should it occur. However, unabated inflammation can be deleterious and contribute to injury and pathology. Interleukin-1ß (IL-1ß), a prototypical "pro-inflammatory" cytokine, is essential to cellular defense and tissue repair in nearly all tissues. With respect to brain, however, studies suggest that IL-1ß has pleiotrophic effects. It acts as a neuromodulator in the healthy central nervous system (CNS), has been implicated in the pathogenic processes associated with a number of CNS maladies, but may also provide protection to the injured CNS. Here, we will review the physiological and pathophysiological functions of IL-1ß in the central nervous system with regard to synaptic plasticity. With respect to disease, emphasis will be placed on stroke, epilepsy, Parkinson's disease and Alzheimer's disease where the ultimate injurious or reparative effects of IL-1ß appear to depend on time, concentration and environmental milieu.

Neuromodulatory role of endogenous interleukin-1ß in acute seizures: possible contribution of cyclooxygenase-2.

The function of endogenous interleukin-1ß (IL-1ß) signaling in acute seizure activity was examined using transgenic mice harboring targeted deletions in the genes for either IL-1ß (Il1b) or its signaling receptor (Il1r1). Acute epileptic seizure activity was modeled using two mechanistically distinct chemoconvulsants, kainic acid (KA) and pentylenetetrazole (PTZ). KA-induced seizure activity was more severe in homozygous null (-/-) Il1b mice compared to their wild-type (+/+) littermate controls, as indicated by an increase in the incidence of sustained generalized convulsive seizure activity. In the PTZ seizure model, the incidence of acute convulsive seizures was increased in both Il1b and Il1r1-/- mice compared to their respective +/+ littermate controls. Interestingly, the selective cyclooxygenase (COX)-2 inhibitor, rofecoxib, mimicked the effect of IL-1ß deficiency on PTZ-induced convulsions in Il1r1+/+ but not -/- mice. Together, these results suggest that endogenous IL-1ß possesses anticonvulsive properties that may be mediated by arachidonic acid metabolites derived from the catalytic action of COX-2.

Prophylactic, prandial rofecoxib treatment lacks efficacy against acute PTZ-induced seizure generation and kindling acquisition.

PURPOSE: The goal of this study was to determine whether prophylactic prandial administration of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, could alter seizure generation, kindling acquisition, and/or kindling maintenance in the mouse pentylenetetrazole (PTZ) epilepsy model. METHODS: Male CD-1 mice were fed ad libitum with control chow or chow formulated to deliver 30 mg/kg/day rofecoxib. After 5 days, mice were treated with a single dose of 40 or 55 mg/kg PTZ (acute paradigm) or 40 mg/kg PTZ delivered daily (kindling paradigm). Seizure severity was scored on a four-point behavioral scale and COX-2 expression was assessed in brain slices from a subset of mice 3 h or 72 h after acute PTZ or following establishment of kindling. KEY FINDINGS: Hippocampal COX-2 expression was transiently upregulated 3 h after an acute PTZ-induced convulsion and returned to baseline levels within 72 h, whereas it remained elevated for at least 72 h after the final seizure in the kindling paradigm. Despite this increase, chronic rofecoxib treatment did not attenuate the severity of acute PTZ-induced seizures and failed to alter kindling development or maintenance. SIGNIFICANCE: The present study demonstrates that prophylactic, prandial rofecoxib treatment lacks efficacy against acute PTZ-induced seizure generation and kindling acquisition, and does not reverse the kindled state once established.

The N-methyl-D-aspartate receptor inhibitory potencies of aromatic inhaled drugs of abuse: evidence for modulation by cation-pi interactions.

Benzene and several close structural analogs are inhaled drugs of abuse with general anesthetic activity. By virtue of their pi electron clouds, they may engage in attractive electrostatic interactions with cationic atomic charges on protein targets. In this study, we tested the hypothesis that inhaled drugs of abuse inhibit human N-methyl-D-aspartate (NMDA) receptors with potencies that correlate with their abilities to engage in cation-pi interactions. Electrophysiological techniques were used to define the NR1/NR2B NMDA receptor inhibitory concentrations of volatile benzene analogs, and computer modeling was used to quantify their abilities to engage in cation-pi interactions and their molecular volumes. In addition, each compound's octanol/gas partition coefficient (a measure of hydrophobicity) was quantified. All 18 compounds inhibited human NR1/NR2B NMDA receptors reversibly and in a concentration-dependent manner. NMDA receptor inhibitory potency correlated strongly with the ability to engage in cation-pi interactions, weakly with hydrophobicity, and was independent of molecular volume. This is consistent with the hypothesis that cation-pi interactions enhance the binding of inhaled drugs of abuse to the NMDA receptor and suggests that the receptor binding site(s) for these drugs possesses significant cationic character.

Proteomic mapping provides powerful insights into functional myelin biology.

Myelin is a dynamic, functionally active membrane necessary for rapid action potential conduction, axon survival, and cytoarchitecture. The number of debilitating neurological disorders that occur when myelin is disrupted emphasizes its importance. Using high-resolution 2D gel electrophoresis, mass spectrometry, and immunoblotting, we have developed an extensive proteomic map of proteins present in myelin, identifying 98 proteins corresponding to at least 130 of the approximately 200 spots on the map. This proteomic map has been applied to analyses of the localization and function of selected proteins, providing a powerful tool to investigate the diverse functions of myelin.

Modulation of GABA(A) receptor function by nonhalogenated alkane anesthetics: the effects on agonist enhancement, direct activation, and inhibition.

UNLABELLED: At clinically relevant concentrations, ethers, alcohols, and halogenated alkanes enhance agonist action on the gamma-aminobutyric acid(A) (GABA(A)) receptor, whereas nonhalogenated alkanes do not. Many anesthetics also directly activate and/or inhibit GABA(A) receptors, actions that may produce important behavioral effects; although, the effects of nonhalogenated alkane anesthetics on GABA(A) receptor direct activation and inhibition have not been studied. In this study, we assessed the abilities of two representative nonhalogenated alkanes, cyclopropane and butane, to enhance agonist action, directly activate, and inhibit currents mediated by expressed alpha(1)beta(2)gamma(2L) GABA(A) receptors using electrophysiological techniques. Our studies reveal that cyclopro- pane and butane enhance agonist action on the GABA(A) receptor at concentrations that exceed those required to produce anesthesia. Neither nonhalogenated alkane directly activated nor inhibited GABA(A) receptors, even at concentrations that approach their aqueous saturated solubilities. These results strongly suggest that the behavioral actions of nonhalogenated alkane anesthetics do not result from their abilities to enhance agonist actions, directly activate, or inhibit alpha(1)beta(2)gamma(2L) GABA(A) receptors and are consistent with the hypothesis that electrostatic interactions between anesthetics and their protein binding sites modulate GABA(A) receptor potency. IMPLICATIONS: When normalized to either their in vivo anesthetic potencies or hydrophobicities, cyclopropane and butane are 1-1.5 orders of magnitude less potent enhancers of agonist action on alpha(1beta2gamma2L) GABA(A) receptors than isoflurane. Additionally, cyclopropane and butane fail to directly activate or inhibit receptors, even at near aqueous saturating concentrations. Thus, it is unlikely that either enhancement or inhibition of the most common GABA(A) receptor subtype in the brain accounts for the behavioral activities of cyclopropane and butane.

Nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes inhibit alpha(4)beta(2) neuronal nicotinic acetylcholine receptors.

UNLABELLED: The nonhalogenated anesthetic alkanes, cyclopropane and butane, do not enhance gamma-aminobutyric acid-elicited GABAergic currents, suggesting that these agents produce anesthesia via interactions with other molecular targets. Perhalogenated nonimmobilizing alkanes, such as 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane, also fail to enhance GABAergic currents, but display specific behavioral effects that are distinct from those of structurally similar anesthetics. At concentrations predicted to be anesthetic, 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane produce amnesia but fail to produce immobility. Neuronal nicotinic acetylcholine (nACh) receptors are sensitive to many anesthetics and are thought to have an important role in learning and memory. We postulated that neuronal nACh receptors might mediate the common amnestic action of nonhalogenated and perhalogenated alkanes. To test the hypothesis that neuronal nACh receptors have a role in mediating the behavioral effects of general anesthetics and nonimmobilizers, we quantified the inhibitory potencies of nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes on currents mediated by alpha(4)beta(2) neuronal nACh receptors. Our studies reveal that anesthetics and nonimmobilizers significantly inhibit alpha(4)beta(2) neuronal nACh receptors at concentrations that suppress learning and with potencies that correlate with their hydrophobicities. These results support the hypothesis that alpha(4)beta(2) neuronal nACh receptors mediate the amnestic actions of alkanes but not their immobilizing actions. IMPLICATIONS: The results of this study suggest that the immobilizing actions of general anesthetics do not result from the inhibition of alpha(4beta2) neuronal nicotinic acetylcholine receptors. However, the inhibition of neuronal nicotinic acetylcholine receptors may account for the amnestic activities of general anesthetics and nonimmobilizers.

The role of electrostatic interactions in governing anesthetic action on the torpedo nicotinic acetylcholine receptor.

UNLABELLED: Isoflurane and normal alkanols reduce the apparent agonist dissociation constant (Kd) of the nicotinic acetylcholine receptor (nAChR) at clinically relevant concentrations, whereas cyclopropane and butane do not. This suggests that electrostatic (hydrogen bonding and/or dipolar) interactions modulate anesthetic potency in this model receptor system. To further define the nature of these interactions, we quantified the potencies with which a heterologous group of general anesthetics reduces the nAChR's apparent Kd for acetylcholine. We assessed the importance that an anesthetic's molecular volume, ability to donate a hydrogen bond (hydrogen bond acidity), ability to accept a hydrogen bond (hydrogen bond basicity), and dipole moment play in determining aqueous potency. We found that aqueous anesthetic potency increases with molecular volume and decreases with hydrogen bond basicity but is unaffected by dipole moment and hydrogen bond acidity. These results suggest that anesthetics reduce the apparent agonist Kd of the nAChR by binding to a site that has a dipolarity and ability to accept hydrogen bonds that are similar to those of water, but a hydrogen bond-donating capacity that is less. IMPLICATIONS: Anesthetics representing a wide range of chemical classes reduce the apparent agonist dissociation constant of the Torpedo nicotinic acetylcholine receptor with aqueous potencies that are governed by their molecular volumes and hydrogen bond basicities. However, neither their hydrogen bond acidities nor dipole moments influence aqueous potency.