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  Methods for treating neuropathological states and neurogenic inflammatory states and methods for identifying compounds useful thereinUSPTO Application #: 20060142213Title: Methods for treating neuropathological states and neurogenic inflammatory states and methods for identifying compounds useful therein Abstract: The present invention provides methods for treating neuropathological states and neurogenic inflammatory states in a subject. The present invention also provides methods for identifying compounds that can be used to treat such states. Preferably, the compounds alter the distribution of NMDA glutamate receptor NR1 subunit in cells, and/or alter the production of TNFα by cells. (end of abstract) Agent: Mueting, Raasch & Gebhardt, P.A. - Minneapolis, MN, US Inventors: Karin Westlund High, Giulio Taglialatela USPTO Applicaton #: 20060142213 - Class: 514027000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Oxygen Of The Saccharide Radical Bonded Directly To A Nonsaccharide Hetero Ring Or A Polycyclo Ring System Which Contains A Nonsaccharide Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20060142213. Brief Patent Description - Full Patent Description - Patent Application Claims
CONTINUING APPLICATION DATA [0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60/210,413, filed Jun. 8, 2000, and U.S. Provisional Application Ser. No. 60/225,702, filed Aug. 16, 2000, which are incorporated by reference herein. BACKGROUND [0003] Glutamate is the primary transmitter of most neurons in the nervous system, including those involved in sensing pain. Glutamate is typically locked up in nerve endings and is released in very small amounts at nerve junctions to signal when a nerve is activated. Glutamate attaches itself to specific receptive docking sites on the next nerve in sequence. In the case of ionotropic glutamate receptors the docking process allows a tiny channel to open, and a charge is transferred by sodium and calcium ions as a tiny electrical current. In the case of pain, the chemical message is converted to electrical energy and carried by the pain transmission nerves to specific sites in the nervous system that interpret the signals as pain. Typically, the precision of the nervous system depends on this event taking place in microseconds. The glutamate receptor site then closes rapidly, resetting for the next neuronal event. [0004] Glutamate is released by neurons in high concentrations in each case of persistent pain and neural injury. In cases of severe pain, inflammation, and tissue damage, such as with arthritis, spinal cord injury or head injury, large amounts of glutamate escape and can be destructive. The damage that occurs in the presence of high glutamate concentrations translates into long-lasting pathological levels of pain and nervous tissue damage. These events also involve many other neuronal and inflammatory agents, but excess glutamate is an initiator in these long-term events that enhances the pain signal. In addition to prolonged pain, excessive glutamate for extended periods of time, as in severe injury, will poison and kill nerve cells. This is evident in cases of head injury and spinal cord damage where the secondary destruction by the presence of excess glutamate amplifies the initial damage caused by the event itself. [0005] Nerve activation under normal conditions involves a glutamate receptor, non-NMDA ionotropic glutamate receptor, allowing sodium to enter the cell to activate the cell. Another glutamate receptor, NMDA ionotropic glutamate receptor, is a channel on the cell membrane allowing passage of calcium ions that carries a stronger electrical signal in normal transmission. This particular glutamate receptor, the NMDA glutamate receptor, is composed of two sets of two protein molecules, the NR1 and NR2 NMDA glutamate receptor subunits. They bind tightly to one another to form the ring through which the calcium signal is carried. A fifth subunit protein may sometimes accompany the four functional subunits. [0006] In the case of persistent pain, the continual presence of glutamate will initiate a cascade of additional events beyond simple nervous event signaling. In addition to activation of both ion channel type glutamate receptors, other types of glutamate receptor complexes are activated called metabotropic receptor proteins. These are receptor proteins that when also activated have longer-lasting effects, sit adjacent to the NMDA glutamate receptor and can release stores of calcium inside the cell. Cascades of intracellular processes are then initiated. Most importantly, these cascades are capable of influencing the entire behavior of the nerve cell in a longer-lasting way if they signal and direct the future activities of the cell long-term by communicating with the cell nucleus. [0007] Memory and learning function are closely related to persistent pain mechanisms. Memory and learning involve both types of ion transporting glutamate receptors, the ionotropic glutamate receptors, in the hippocampus and cortex of the brain. The cells in the hippocampus are activated by glutamate as the signal relaying transmitter. If the activation of this brain region is strong enough and persistent enough, then both ionotropic glutamate receptor types are activated to achieve a long-term memory of the event through a new "hard-wired" cortical neuronal circuit. This is similar to the "hard-wired" memory of the painful event that becomes a persistent process in the pain transmission circuitry, referred to as sensitization on the cellular level and persistent central pain state on the whole animal level. Further activation of the event to the point of becoming pathological amounts of chronic pain occurs by activation of other neuronal receptors, preferably in this case the metabotropic glutamate receptor producing long-term nuclear and cellular changes including the release of intracellular calcium and regulation of many enzymes (especially kinases and phosphatases). The cells are then overactivated and a sensitized, neuropathological state develops. In the neuropathological state the pain message is enhanced and may remain this way for a prolonged period of time. [0008] The aim of basic science research in the field of pain is to provide better treatment for the millions of people who suffer from persistent pain. Current methods for pain control mainly use traditional pharmacological approaches in which small molecules are taken orally. Many of these medicines treat some of the symptoms of pain by attaching themselves to receptor molecules on the cell surface, including the glutamate receptor, in an attempt to compete with the nerves own transmitter chemicals. Currently, little is known about the processes that have already occurred within the cell that are already initiated after neuropathological neural signaling events have occurred and by which the high degree of persistent pain continues. A better understanding of these events would allow for more effective pain control. SUMMARY OF THE INVENTION [0009] This invention represents a significant advance in the art of identifying agents that can be used for the treatment of certain conditions, including neuropathological states and neurogenic inflammatory states. [0010] The present invention provides a method for treating a neuropathological state in a subject. The method includes administering to the subject an effective amount of a tyrosine kinase inhibitor. The neuropathological state may be, for instance, persistent pain, arthritis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, pancreatitis, asthma, stroke, brain injury, spinal cord injury, epileptogenesis, or viral invasion. The tyrosine kinase inhibitor may be, for instance, Genistein, Lavendustin A, K252a, or combinations thereof. [0011] In another aspect, a method for treating a neuropathological state in a subject includes administering to the subject an effective amount of a compound that decreases the amount of NR1 subunit associated with a nucleus of a cell of the subject wherein the cell contains an NMDA glutamate receptor. The cell may be a neuron. Optionally, the neuron is a sensitized neuron or is prevented from being converted to a sensitized neuron. The compound may be a tyrosine kinase inhibitor such as Genistein, Lavendustin A, K252a, or combinations thereof. [0012] In a further aspect, a method for treating a neuropathological state in a subject includes administering to the subject an effective amount of a compound that decreases the amount of Tumor Necrosis Factor alpha (TNF.alpha.) produced by a cell of the subject. The cell may be a synovial cell. The cell may optionally include an NMDA glutamate receptor. The compound may be a tyrosine kinase inhibitor such as Genistein, Lavendustin A, K252a, or combinations thereof. [0013] The present invention also provides a method for identifying a compound that alters NR1 subunit distribution in a cell. The method includes contacting a cell with an effective amount of the compound, activating an NMDA glutamate receptor present on the cell, and detecting the distribution of NR1 subunit in the cell wherein detection of an alteration in the distribution of NR1 subunit in the cell contacted with the compound relative to the distribution of NR1 subunit in a cell not contacted with the compound indicates an alteration in the distribution of NR1 subunit. The cell may be a neuron. The compound may be a tyrosine kinase inhibitor. [0014] The present invention provides a method for identifying a compound that alters the production of TNF.alpha. by a cell. The method includes contacting a cell with an effective amount of the compound, activating an NMDA glutamate receptor present on the cell, and detecting the amount of TNF.alpha. produced by the cell wherein detection of an alteration in the amount of TNF.alpha. produced by the cell contacted with the compound relative to the amount of TNF.alpha. produced by a cell not contacted with the compound indicates an alteration in the amount of TNF.alpha. produced by the cell. The cell may be a synovial cell. [0015] The present invention provides a method for treating a neurogenic inflammatory state in a subject. The method includes administering to the subject an effective amount of a compound that decreases the amount of TNF.alpha. produced by a cell of the subject wherein the cell contains an NMDA glutamate receptor. The compound may be a tyrosine kinase inhibitor. [0016] The present invention provides a method for treating arthritis in a subject. The method includes administering to the subject an effective amount of a compound that decreases the amount of TNF.alpha. produced by a synovial cell of the subject. The compound may be a tyrosine kinase inhibitor. [0017] The present invention provides a method for altering NR1 subunit distribution in a cell. The method includes contacting a cell with an effective amount of the compound, activating an NMDA glutamate receptor present in the cell, and detecting the distribution of NR1 subunit in the cell wherein detection of an alteration in the distribution of NR1 subunit in the cell contacted with the compound relative to the distribution of NR1 subunit in a cell not contacted with compound indicates an alteration in the distribution of NR1 subunit. The NR1 subunit associated with a nucleus of a cell of the subject may be increased or decreased. Definitions [0018] As used herein, the terms "neuropathological state" and "neuropathological condition" are used interchangeably and refer to functional disturbances and/or pathologic changes in a subject's nervous system. Examples of functional disturbances include persistent pain, an inflammatory state, brain injury, spinal cord injury, epileptogenesis, and viral invasion. Examples of pathological changes include the presence of persistent pain due to functional disturbances and a decrease in mental function due to epileptogenesis, memory disturbances, and aging. [0019] As used herein, "neurogenic inflammatory state" refers to conditions where high concentrations of a glutamate receptor agonist are present (for instance, released by a neuron) and interact with a glutamate receptor, preferably an NMDA glutamate receptor, that is present on a cell. The interaction of the agonist with the glutamate receptor results in the production of cytokines, preferably, tumor necrosis factor .alpha. (TNF.alpha.) by the cell. Types of neurogenic inflammatory states include, for instance, arthritis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, pancreatitis, asthma, stroke, brain injury, and viral invasion. [0020] As used herein, an "effective amount" is an amount effective to decrease or prevent in a subject the symptoms associated with a condition described herein. [0021] As used herein, the term "glutamate receptor" refers to a receptor present on the outer cellular membrane of a cell that binds glutamate, glutamate agonists, or glutamate antagonists. There are two types of glutamate receptors, ionotropic and metabotropic. Binding of agonist, for instance glutamate, N-methyl-D-aspartate, aspartate (NMDA), glycine, serine, by an ionotropic glutamate receptor results in channel opening and the subsequent flow of ions through the channel. Binding of agonist, for instance glutamate, (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), quisqualic acid or ibotenic acid by a metabotropic glutamate receptor results in phosphoinositide hydrolysis and intracellular calcium mobilization. "Activation" of a transmitter-gated channel, for instance a glutamate receptor, refers to the opening of the channel or initiation of transmitter related events. Preferably, the glutamate receptor is an NMDA glutamate receptor. Continue reading... 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