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Methods of using ryanodine antagonists in treating neural injury

Inactive Publication Date: 2006-02-09
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] A new method of protecting the neurons in the retina and other parts of the brain of a mammal from noxious provocations has been discovered. The present method uses a ryanodine receptor antagonist to prevent or ameliorate damage to CNS neurons caused by noxious provocations that induce excessive calcium release from intracellular stores via ryanodine receptor channels. These noxious provocations, including excitotoxicity, ischemia, hypoxia, mitochondrial dysfunction, and oxidative injury, are associated with acute and chronic neural disorders, including glaucoma, diabetic retinopathy, age-related macular degeneration (ARMD), stroke, acute brain trauma, Alzheimer's disease, Parkinson's disease, and Huntington's disease. The method comprises administering to the mammal either systemically, topically, epidurally or by intrabulbar injection an effective amount of one or more ryanodine receptor antagonists, such as dantrolene (see below for details).

Problems solved by technology

Over stimulation of the NMDA receptor resulting from either excessive release or reduced reuptake of glutamate causes intracellular calcium overload that can eventually lead to neuronal death.
The underlying causes for glaucoma are still not well understood.
Thus, it is evident that there is an unmet need for agents that have neuroprotective effects that can stop or retard the progressive damage to CNS neurons resulting from abnormally elevated intracellular free calcium caused by various noxious provocations.

Method used

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  • Methods of using ryanodine antagonists in treating neural injury
  • Methods of using ryanodine antagonists in treating neural injury
  • Methods of using ryanodine antagonists in treating neural injury

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0039] Experimental Procedure for Measuring Neural Protection in Rabbit Model.

[0040] To evaluate in vivo neuroprotective effects of dantrolene (DTL) on NMDA-induced injury of RGCs an imaging method to count cell numbers at the RGC layer in the isolated retinas was developed. Briefly, two weeks following intravitreal injection of vehicle or various test agents, a rabbit was euthanized and the treated eye was enucleated. A piece of retina (8 mm in diameter) was cut immediately below the optic nerve head, flat-mounted in a plastic chamber filled with HEPES-buffered Ames medium, and imaged at 25 fields in a 5×5 array with a 40× water immersion objective using an Olympus microscope (BX50WI) equipped with an epi-fluorescence unit. The images were taken with a Hamamatsu C4742-95 digital camera and Image-Pro Plus software (V4.5). The total number of neurons at the ganglion cell layer in these 25 fields was counted. The same measurements were conducted in one control group (rabbits treated ...

example 2

[0042] This example shows that the ryanodine receptor channel antagonist dantrolene protects retinal ganglion cells (RGCs) from glaucomatous injury in a rat glaucoma model (Chronic Ocular Hypertension model-COHT). In a rat model of glaucoma, RGC injury is induced by high intraocular pressure (IOP). In the control glaucoma animals (COHT-C) high IOP produced 33% loss of RGC at the end of 3 week study. Oral administration of dantrolene at 7.5 mg / kg / day (COHT-DTL) for the duration of the experiment reduced RGC loss to 9%, whereas oral administration of the vehicle (COHT-V) has no protection. This dantrolene protection is at least as good as memantine (COTH-MEM) at 10 mg / kg / day. The results are shown in FIG. 2.

example 3

[0043] Assay for Selecting Ryanodine Antagonists Other than Dantrolene.

[0044] Assays for determining ryanodine antagonist may be conducted following procedures modified from that described by Laver et al., (J. Physiol. 537:763-778, 2001). Briefly, purified ryanodine receptor-channel complexes are incorporated into planar phospholipid bilayers with resting calcium gradient similar to that in a normal neuron at rest (100 nM cytoplasmic and 1 mM luminal). The level of channel activation can be determined in the presence of various ligands that activate ryanodine receptors. Effective antagonistic action of the compounds to be selected can be determined by a reduction of agonist-induced activation of the channel. The specificity of the antagonists can be determined by commercially available standard screens, such as NovaScreens.

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Abstract

The present invention provides a method of providing neuroprotection to a mammal comprising administering to said mammal suffering from or at risk of suffering a noxious action on its nerve cells an effective amount of a ryanodine antagonist, e.g. dantrolene, to inhibit or prevent nerve cell injury or death.

Description

RELATED APPLICATIONS [0001] This is a continuation in part application of Ser. No. 10 / 189,676, filed Jul. 3, 2002, and incorporated in its entirety by reference herein.FIELD OF THE INVENTION [0002] The present invention relates to neurology and ophthalmology, and more specifically to protection of neural tissues from injuries caused by abnormal elevation of intracellular free calcium through calcium release from intracellular stores under disease conditions, including stroke, acute brain trauma, Alzheimer's disease, Parkinson's disease, glaucoma, diabetic retinopathy, and age-related macular degeneration. BACKGROUND OF THE INVENTION [0003] There is compelling evidence that abnormally elevated intracellular free calcium is one of the early events in the chain of reactions leading to neuronal damage under pathological conditions that range from acute neural injuries, such as stroke, to more chronic indications, such as Alzheimer's disease. High intracellular free calcium can cause mit...

Claims

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Application Information

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IPC IPC(8): A61K31/655A61K31/24A61K31/13C07D405/12A61K31/4166A61K31/4178A61K45/00A61K45/06A61P25/00A61P25/16A61P25/28A61P27/02A61P27/06
CPCA61K31/4178A61K31/4166A61P25/00A61P25/16A61P25/28A61P27/02A61P27/06
Inventor DONG, CUN-JIANHARE, WILLIAM A.
Owner ALLERGAN INC
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