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Methods and Compositions for Treating Thalamocortical Dysrhythmia

a technology of thalamocortical dysrhythmia and composition, applied in the field of medical sciences generally and neurophysiology and neuropharmacology, can solve the problems of abnormal neuronal oscillation, uncoordinated electrical activity, and impair the motor and cognitive skills that are controlled by those regions of the cortex

Inactive Publication Date: 2008-10-30
NEW YORK UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0045]FIG. 6A are schematic representations of recordings from an experiment showing the effect of tetrodotoxin (“TTX”) on low-threshold calcium current using a current clamp technique, in both wild type (top) and alpha1A-KO calcium channel knockout (bottom) mice

Problems solved by technology

In particular, these and other neurological disorders occur when the coordinate, controlled electrical activity at the cortical level of the brain becomes disrupted, thereby leading to uncoordinated electrical activity and abnormal neuronal oscillation.
At the macrocellular level, the abnormal rhythmicity interferes with the communication among and between different regions of the brain, and thereby impairs the motor and cognitive skills that are controlled by those regions of the cortex.
However, many of such drugs are limited in their effectiveness and by their significant side effects.
For example, some of these drugs are known to cause lightheadedness, depression insomnia, weakness, fatigue, hallucinations, side-effects which severely limit their use in human population.
However, beta blockers can cause changes in blood pressure and heart rate, and are contraindicated in patients with heart block, asthma, and congestive heart failure.
In addition, some anticonvulsants can cause acute nausea and vomiting, fatigue, sleepiness, confusion and incoordination, while others can cause memory and speech abnormalities, sedation, incoordination, and metabolic dysfunction.
Such procedures carry a high risk of infection and bleeding or equipment malfunction.
Additionally, many existing treatments for some neurological disorders are poorly effective in that they do not stop the disorders completely, and in most instances, they do not prevent or even delay the progression of the disease.

Method used

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  • Methods and Compositions for Treating Thalamocortical Dysrhythmia
  • Methods and Compositions for Treating Thalamocortical Dysrhythmia
  • Methods and Compositions for Treating Thalamocortical Dysrhythmia

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Brain Slices Containing Ventrobasal Thalamic Nucleus

[0143]Long-Evans rats (two to four weeks old, 40-50 g; either sex; Taconic Farms) and Harley guinea pigs (four to eight weeks old, 50-300 g) were anesthetized with pentobarbital (Nembutal, 120 mg / Kg i.p.), decapitated and the bone and dura mater covering the cortical surface were carefully peeled away. The rostral part of the brain was glued onto microslicer stage of a vibroslicer (Leica Microsistemas, Bannockburn, Ill., USA) containing a low Na+ / high sucrose artificial cerebrospinal fluid (“ACSF”) solution (248 mM sucrose, 26 mM NaHCO3, 1.25 mM NaH2PO4, 5 mM KCl, 3 mM MgSO4, 0.5 mM CaCl2, 10 mM (+)-sodium-L-ascorbate, 3 mM sodium pyruvate and 10 mM glucose, aerated with 95% O2 / 5% CO2 to a final pH of 7.4). 180 μm to 240 μm transverse slices were obtained containing both thalamic and cortical areas. After cut, slices were allowed to recover in an incubation chamber at 37° C. for at least 30 min. containing continuous...

example 2

Whole-Cell Patch Recording Methods

[0144]Patch recordings were performed at 35° C. in a chamber constantly perfused with normal ACSF solution containing carbachol (50 μM-100 μM, a cholinergic agonist, both nicotinic and muscarinic), tetrodotoxin (100 nM-500 nM, a voltage-dependent sodium channel blocker) and an equivalent proportion of the vehicle Tween-80 used to dissolve octanol (Llinás et al. (1982) Nature 297:406-408.). Patch electrodes were made from borosilicate glass and had resistances of 3 to 8 MΩ when filled with either high potassium intracellular solution (130 mM KMeSO3, 10 mM NaCl, 10 mM HEPES, 1 mM EGTA, 4 mM Mg-ATP, 0.4 mM Na-GTP, 2 mM MgCl2, 10 mM sucrose and 10 mM phosphocreatine, pH 7.3, 290 mOsm); or either a high cesium / QX314 intracellular solution (120 mM CsMeSO3, 8 mM NaCl, 10 mM HEPES, 5 mM EGTA, 10 mM TEA-Cl (triethylamine chloride), 4 mM Mg-ATP, 0.5 mM GTP, 7 mM phosphocreatine, pH 7.3 (29 mOsm)). High potassium solution was used when octanol-dependent effect...

example 3

A. Inhibition of Cav3 Plasmalemmal-Bound Calcium Channel With 1-Octanol

[0146]FIGS. 1A and 1B show the patch recording of individual thalamic neurons from the ventrobasal nucleus obtained from the rodents' brain slices prepared according to Example 1. The thalamic nucleus processes the somatosensory information from rodents' whiskers. The effect of 10 μM octanol on calcium channels at two different voltage levels was shown.

[0147]Using a holding level where only low voltage activated calcium currents can be open (−30 mV), octanol blocks peak fast activated Cav3.1 calcium current (ICa) amplitude by about 30% (FIG. 1A). When both low and high voltage activated calcium currents are open, octanol blocks the peak of the fast component (Cav3.1) leaving unchanged the slow component that remains open at the end of the depolarized pulse (−10 mV)( FIG. 1B). Therefore, 1-octanol is shown to specifically block low threshold activated Cav3-type currents from Ventrobasal thalamic neurons.

B. Inhibit...

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Abstract

This invention relates to methods of inhibiting a Cav3 calcium channel in a cell using a C2-C10 alkyl alcohol, or mixtures thereof. This invention further relates to methods of treating a thalamocortical dysrhythmia disorder in a mammal and for treating a neurological disorder in a mammal associated with the thalamocortical dysrhythmia using a C2-C10 alkyl alcohol, a lipophilic molecule with a partition coefficient substantially similar to that of a C2-C10 alkyl alcohol, or mixtures thereof, or a pharmaceutical composition comprising the same.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60 / 906,085 filed on Mar. 9, 2007, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]This invention relates to the medical sciences generally and neurophysiology and neuropharmacology in particular. More specifically, this invention relates to methods and compositions for treating a neurological disorder in a mammal and for an associated thalamocortical dysrhythmia using a C2-C10 alkyl alcohol, or a lipophilic molecule with a partition coefficient substantially similar to that of a C2-C10 alkyl alcohol, or mixtures thereof.BACKGROUND OF THE INVENTION[0003]Neurological disorders that affect the central nervous system, the peripheral nervous system, and the autonomic nervous system strick millions of people worldwide. These varied disorders include, but are not limited to, thalamocortical dysr...

Claims

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Application Information

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IPC IPC(8): A61K33/30A61K31/045G06G7/58A61K33/16A61P25/08A61K31/05A61K31/135A61K31/02A61K31/4045A61K31/137A61K31/381A61K31/4422A61K31/4168A61K31/451A61K31/517A61K31/138A61K31/4525A61K31/66A61K31/08A61K31/4164A61P25/28A61P25/02G01N33/566A61K31/515
CPCA61K31/045A61K45/06A61K2300/00A61P25/00A61P25/02A61P25/06A61P25/08A61P25/10A61P25/16A61P25/18A61P25/24A61P25/28A61P9/12
Inventor LLINAS, RODOLFO R.SUGIMORI, MUTSUYUKIURBANO, FRANCISCO
Owner NEW YORK UNIV
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