Compositions and methods for the treatment of disorders of the central and peripheral nervous systems

Abstract

The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and materials for treating seizure and seizure disorders, epilepsy, status epilepticus, migraine, spreading depression, intracranial hypertension; for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia; for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol; and for treating neuropsychiatric disorders and central nervous system edema by administering agents that modulate ionic concentrations and / or ionic gradients in the brain, particularly ion-dependent or cation-chloride cotransporter antagonists. Electrolyte cotransport antagonists and combinations of such compositions with other agents for treating various conditions are disclosed.

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 056,528, filed Jan. 23, 2002, which claims priority under 35 U.S.C. § 19(e) to U.S. Patent Application No. 60 / 263,830, filed Jan. 23, 2001, and is a continuation-in-part of U.S. patent application Ser. No. 09 / 470,637, filed Dec. 22, 1999, now U.S. Pat. No. 6,495,601, which claims priority under 35 U.S.C. §119(e) to U.S. Patent Application 60 / 113,620, filed Dec. 23, 1998.TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and compositions for treating seizures and seizure disorders, epilepsy, status epilepticus, migraine headache, cortical spreading depression, intracranial hypertension, neuropsychiatric disorders, central nervous system ede...

AI Technical Summary

Benefits of technology

[0023] Selected treatment compositions and methods of the present invention are useful for treating central nervous system conditions, including seizures and seizure disorders, epilepsy, including Status epilepticus, migraine headaches, other types of headaches, cortical spreading depression, intracranial hypertension, neuropsychiatric disorders, and central nervous system edema. Selected treatment compositions and methods of the present invention are also suitable for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol and certain infectious agents, and for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia. According to another embodiment, treatment agents and methods of the present invention improve function in certain cortical tissue, such as in cortical centers of cognition, learning and memory. Additionally, treatment agents and methods of the present invention are useful for treating pain by affecting or modulating the conduction of impulses associated with pain in the peripheral nervous system. Treatment compositions and methods of the present invention may be used therapeutically and episodically following the onset of symptoms, or prophylactically prior to the onset of specific symptoms, and are suitable for both human and veterinary applications.

[0024] Methods and compositions of the present invention, in one aspect, involve treatment of various conditions of the central and peripheral nervous systems via non-synaptic mechanisms and, more specifically, by modulating, generally reducing, the synchronization of neuronal population activity. According to a preferred embodiment, the synchronization of neuronal population activity is modulated by manipulating anionic concentrations and gradients in the central and / or peripheral nervous systems. Ion dependent cotransporter antagonists are suitable treatment compositions, anion cotransporter antagonists are preferred treatment compositions, and cation-chloride cotransporter antagonists are especially preferred treatment compositions. According to one embodiment, Na+, K+, 2Cl− chloride cotransporter antagonists are especially preferred treatment agents for modulating the synchronization of neuronal population activity. Anion cotransporter antagonists are useful for treating conditions such as seizures, epilepsy and status epilepticus, cortical spreading depression, migraine and other types of headaches, intracranial hypertension, neuropsychiatric disorders, central nervous system edema, for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol and certain infectious agents, and for reducing the perception of pain. Chloride cotransporter agonists are preferred treatment agents, and cation-chloride cotransporter agonists are especially preferred treatment agents for improving function in cortical areas associated with cognition, learning and memory, for example.

[0027] In another aspect, methods and compositions of the present invention involve the use of combinations of agents, particularly the combination of an agent employing a non-synaptic mechanism, such as an ion-dependent cotransporter antagonist, with one or more agents employing one or more traditional treatment mechanism(s). Methods for treating seizure disorders and status epilepticus involve administering an ion-dependent cotransporter antagonist, preferably a cation-chloride cotransporter antagonist, in combination with another treatment agent. Furosemide and other loop diuretics, as well as thiazide and thiazide-like diuretics, are suitable cation-chloride cotransporter antagonists. Experimental studies have shown that furosemide treatment produces a transient and early increase in synchronization of neuronal population activity, followed by a persistent and complete disruption of the hypersynchronization characteristic of epileptiform activity. Treatment of status epilepticus, according to one embodiment of the present invention, involves administration of an agent that affects the synchronization, or relative synchrony, of neuronal population activity, such as an ion-dependent cotransporter antagonist, preferably a cation-chloride cotransporter antagonist such as furosemide or a furosemide-related compound, or thiazide or thiazide-like compound, in combination with another agent that may affect a synaptic mechanism, such as a barbiturate, that is capable of treating the symptoms associated with the transient and early increase in synchronization of neuronal population activity observed upon administration of an ion-dependant cotransporter antagonist. In one embodiment, the above-mentioned combination therapy will include the acute administration of a pharmaceutically acceptable hyperosmotic agent, such as mannitol, for enhanced effect.

[0030] Yet another aspect of the present invention involves treatment of neurotoxicity attributable to a variety of chemical and biological agents, as well as some infectious agents. Compositions and methods of the present invention are especially effective in reducing the neurodegenerative effects of acute ethanol ingestion. Additionally, compositions of the present invention may be administered prophylactically to protect cortical tissue from the effects of neurotoxicity attributable, for example, to acute ethanol ingestion. Treatment compositions of the present invention for treating, or for prophylactic administration to protect from neurotoxicity, comprise ion-dependent cotransporter antagonists, preferably cation-chloride cotransporter antagonists. According to a preferred embodiment, agents and methods of the present invention for protecting from neurotoxicity preferentially act on the Na+, K+, 2Cl− chloride-dependent cotransport system of glial cells and have reduced activity on the chloride-dependent cotransport systems of other cells types, such as neurons and renal cells.

[0031] Another aspect of the present invention relates to methods and agents for relieving pain, or the perception of pain, by effecting or modulating propagation of action potentials or conduction of impulses in certain nerve fibers, particularly unmyelinated fibers, in the peripheral nervous system. More specifically, changes in extracellular ionic concentrations and ionic gradients in cells in the peripheral nervous system, affected by ion-dependent cotransporters, diminishes the perception or sensation of pain. Agents of the present invention for treating, or for prophylactic administration to protect from pain, ion-dependent chloride cotransporter antagonists, preferably cation-chloride transporter antagonists, that modulate the extracellular ionic concentration and / or the ionic gradients in the peripheral nervous system. According to a preferred embodiment, compositions of the present invention for treating pain preferentially act on the cation-chloride cotransport system of glial cells, or Schwantz cells, and have reduced activity on the chloride-dependent cotransport systems of other types of cells, such as neurons and renal cells.

[0032] Yet another aspect of the present invention relates to methods and agents for enhancing the function of certain cortical functions, such as, cognitive, learning and memory. Enhanced synchronization of neuronal population activity improves function in centers associated with cognitive abilities, learning and memory in central nervous system cortex. Treatment compositions and methods of the present invention for enhancing cognitive, learning and memory functions involve modulating the synchronization and timing of neuronal population activity, preferably by enhancing synchronization and coordinating timing. According to one embodiment, enhancement of synchronization is achieved by administering an agent capable of modulating extracellular anionic chloride concentrations and ionic gradients in the brain. Ion-dependent cotransporter agonists are preferred treatment agents, and cation-chloride cotransporter agonists are especially preferred. Methods for screening candidate compounds for ion-dependent cotransporter agonist activity are also provided.

Problems solved by technology

Although such loop diuretics produce the desired modulation of the extracellular anionic chloride concentrations and ionic gradients and, hence, modulation of synchronization of neuronal population activity, they may also produce other, undesired effects.

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