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Compositions and methods for promoting neural regeneration

a neural regeneration and composition technology, applied in the field of tissue regeneration, can solve the problems of not being able to grow new neurons or generate new axons, not being able to directly identify multipotential cells, and not being able to define the mechanisms, so as to improve learning and memory function. the effect of recovery

Inactive Publication Date: 2008-03-20
NEUBERGER TIMOTHY +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for promoting tissue regeneration and expression by administering a composition containing a compound of Formula (I) or (II) to a mammal. The compound can be administered to a mammal to promote the regeneration of neural, liver, pancreatic, or muscle tissue, and can also be used to treat decreased neural function caused by trauma, injury, or neurodegenerative diseases. The method involves collecting cells from the mammal and delivering them to the site of injury or to a second mammal. The invention also provides pharmacologically acceptable carriers for the compositions.

Problems solved by technology

Lineage analysis alone, however, does not directly identify the multipotential cells; nor does it define the mechanisms that drive them to different fates.
Much of the adult central nervous system is unable to grow new neurons or generate new axons.
Injuries to neurons involving transection of, or damage to, the axons (termed “axotomy”) characteristically result in retrograde neuronal dysfunction or death to most of these cells.
Such injuries can result, for example, from trauma to the head or spinal cord, or as a consequence of surgical procedures intended to correct certain conditions of the nervous system.
In addition, damage to axons can occur as a result of neurodegenerative disease, excitotoxic injury, or chemotherapy or radiation therapy.
The amount of excitotoxins released increases in response to abnormal conditions (i.e., seizure, hypoglycemia, and the like) and results in neural loss in the areas of concentration.
While transplantation of nervous tissue to the spinal cord has been attempted on animals and has been shown to improve the regeneration after an injury, the functional recovery after such transplantation is often deceptive and improvement of this method is needed before it can be attempted on patients.
For example, considering that neuron growth during development requires stimulation, for example by Nerve Growth Factor (NGF), it is not fully known whether stimulation of the regrowth of mature CNS neurons will be limited by compromised access of neurons to stimulatory mechanisms, in addition to inhibitory proteins in the CNS.
Thus, it is not known whether neutralizing the inhibitory action of certain CNS proteins will adequately promote functional neural regeneration in vivo.

Method used

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  • Compositions and methods for promoting neural regeneration
  • Compositions and methods for promoting neural regeneration
  • Compositions and methods for promoting neural regeneration

Examples

Experimental program
Comparison scheme
Effect test

example 1

In Vitro Experiment

Embryonic Day 18 Cortical Neuron Culture

[0128] CNS tissue was harvested from embryonic day 18 (E-18) rat pups (Taconic Labs) using sterile technique and was stored in ice cold Hank's Balanced Salt Solution (HBSS—Gibco). Brains were removed from the cranium of 10 embryos, and the meninges removed to expose the underlying cortex. Cortex was isolated from the rest of the brain and stored in ice cold HBSS. After all material was collected, the tissue was minced and trypsinized using 0.1% trypsin (Sigma) for 30 minutes at 37° C. Trypsin action was inhibited by adding 0.5 mg / ml soybean trypsin inhibitor (Gibco). Tissue was rinsed with HBSS and triturated using a flame narrowed Pasteur pipette coated with fetal bovine serum (FBS—MediaTech).

[0129] Dissociated cells were counted and plated into 24 well cluster plates in DMEM (MediaTech) plus 10% FBS (MediaTech) at a density of 5×105 cells per well. Twenty-four well cluster plates were coated with poly-D-lysine prior to ...

example 2

In Vitro Experiment

Neonatal Astrocytes

[0133] Post natal day 5 rat pups (Taconic Labs) were decapitated, skin covering the cranium was removed so the bone over top the brain could be opened. Using a sterile spatula, the brain was extracted from the opened cranium and transferred to a 60 mm petri dish (Corning) containing sterile, ice cold Hank's balanced salt solution (HBSS). The meningial tissue was removed from the cortex, the cortex was gently teased away from the subcortical structures and transferred to a new 60 mm petri dish containing ice cold HBSS. Using a pair of fine, curved forceps, the desired cortical material was pinched from the remainder of the cortex and transferred to a new 60 mm petri dish containing ice cold HBSS. For most experiments, only tissue in the immediate vicinity of the subventricular zone was collected while in a few experiments, almost the entire cortex was pinched leaving only the outer most layer of cortical tissue behind. After harvesting all cort...

example 3

In Vivo Experiment

Spinal Cord Injury Treatment

[0136] Fischer F344 female rats (Taconic, Germantown N.Y.) weighing 175-200 g were subjected to 25 mm weight drop contusion injury as previously described (Gruner J A, J. Neurotrauma, 1992 Summer; 9(2):123-8) with slight modifications. Briefly, under isoflurane anethesia, a laminectomy exposing the T8-9 spinal cord segment was performed and a rod weighing 10 g was dropped on the exposed cord from 25 mm height. The rod diameter at its end (where cord-rod interaction takes place) is 2.8 mm. A total of 12 rats were injured. Four animals were used as donor animals, eight as recipients. Two donor animals were administered N-[4-[(4-fluorophenyl)sulfonyl]phenyl]acetamide at a dose of 100 mg / kg orally, and two other animals were treated with vehicle (cyclodextrin, 45% in distilled sterile water). Five days following donor treatment and four weeks following injury, donor animals were euthanized with CO2 according to the Guidelines set by the Pa...

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Abstract

The present invention relates to compositions and methods for promoting tissue regeneration, preferably neural tissue regeneration. Compositions of the invention include (i) certain diphenyl sulfides, diphenyl sulfoxides, diphenyl sulfones, and sulfide, sulfoxide and sulfones of dibenzothiophene and thioxanthene, as well as various analogues and derivatives of these compounds; (ii) one or more cells harvested from an animal or organism subsequent to the administration of a composition comprising a compound of (i); or (iii) any combination of (i) and (ii). The invention can be useful in treating decreases in neuronal function, for example from injury or disease.

Description

[0001] The present invention relates to promoting tissue regeneration, such as neural tissue or liver tissue regeneration. More specifically, the present invention employs (i) certain diphenyl sulfides, diphenyl sulfoxides, diphenyl sulfones, and sulfide, sulfoxide and sulfones of dibenzothiophene and thioxanthene. [0002] The nervous system consists essentially of two categories of cells, neurons and glial cells. During neuronal development, immature nerve cell bodies migrate along glial cells to a location in the brain, where neurite processes (dendrites and axons) grow out from the nerve cell body. A growth cone at the tip of each process guides the path taken by each process, determining the path of neuron growth. A number of factors influence the path of neuron growth, including nerve growth factor (NGF) and local contact with cell-cell adhesion molecules, contact with extracellular matrix molecules and various other forms of chemotactic guidance. Cell-cell adhesion molecules th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/41A61K31/155A61K31/16A61P25/00C12N5/00A61K31/4178A61K31/381A61K31/255A61K31/382A61K31/415A61K31/47
CPCA61K31/255A61K31/47A61K31/415A61K31/382A61P25/00
Inventor NEUBERGER, TIMOTHY J.HERZBERG, URIMALLON, VERONICA
Owner NEUBERGER TIMOTHY
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