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Sigma ligands for neuronal regeneration and functional recovery

a neuronal regeneration and functional recovery technology, applied in the field of treatment, can solve problems such as paralysis, speech problems, dementia, etc., and achieve the effect of enhancing functional recovery and neuronal regeneration

Inactive Publication Date: 2005-02-10
MS SCI CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods and compositions for treating neurodegenerative diseases. The sigma receptor ligands of the invention enhance functional recovery and neuronal regeneration. These molecules can be delivered alone or in combination with additional agents, and are used as neuronal regeneration agents for the treatment of neurodegenerative diseases such as those resulting from ischemic strokes or other insults that injure neurons.

Problems solved by technology

Depending on the area of the brain that is damaged, a stroke can cause coma, paralysis, speech problems and dementia.

Method used

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  • Sigma ligands for neuronal regeneration and functional recovery
  • Sigma ligands for neuronal regeneration and functional recovery

Examples

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example 1

Animal Models for Neuronal Regeneration (Functional Recovery)

Male 3 months old SHR (spontaneous hypertensive) rats are used for induction of stroke by MCA occlusion. This is the preferred strain since most stroke patients are hypertensive. The animals are anesthetized with Methohexital and a small craniectomy is made above the zygmotic arch to expose the middle cerebral artery, which is occluded with a 10-0 monofilament nylon thread distal to the origin of the striatal branches. The rats are not intubated and no catheters are inserted. Following MCA occlusion a large and reproducible infarct is obtained, leading to a robust sensorimotor deficit. The animals are kept on a 6 hr light / 18 h dark cycle with free access to food and water. At two days after the MCAO the rats are treated with the compound I, II, III, IV, V, VI, VII, VIII, or IX (0.03-10 mg / kg) s.c. or p.o. and a control group is given saline for 2-8 weeks. At 2, 4, 6 and 8 weeks animals are tested in the rotating pole or...

example 2

Evidence of Neuronal Regeneration in Rats Treated with Siramesine

1. Morris Water Maze

The Morris water maze was used to assess functional recovery, in particular recovery in a cognitive skill, in hypertensive rats after exposure to permanent middle artery occlusion (MCAO), a model of ischemic stroke.

Forty three hypertensive rats were exposed to permanent middle artery occlusion (MCAO). Starting at two days after occlusion and continuing for 14 days, Siramesine was administered p.o. in doses of 0.3 mg / kg (14 rats) or 1.0 mg / kg (14 rats). In a control group (15 rats), vehicle only was administered. On day 35 after permanent MCAO, the rats were assessed for their performance in the Morris Water Maze Test.

In the test, the rats were given a series of 6 trials, 1 hour apart in a large dark-colored tank (200 cm in ) filled with clear water at a temperature of 22.0±1.5° C. A 12×12-cm submerged platform (2 mm below the water surface) was placed in the northwest quadrant of the pool. ...

example 3

Gene Expression Studies

The Ethics Committee for Animal Research at Lund University approved the experimental protocol. Six-month-old SHR (spontaneous hypertensive rats), obtained from Mollegard Breeding Center, Ejby, Denmark, 2 months earlier and preoperatively housed in standard cages (550×350×200 mm, 3 to 4 rats in each cage), were anesthetized with methohexital sodium (Brietal, 37° C.) 50 mg / kg intraperitoneally. The right MCA was accessed via a small craniotomy, and the artery was ligated distal to the striatal arteries, causing a neocortical infarct. The mean surgery time was about 20 minutes and body temperature was maintained close to 37° C. Postoperatively, rats were kept in individual cages for 24 hours. The rats subjected to MCA occlusion (MCAO) were either returned to standard environment (SE), or were placed in a large, vertical, enriched-environment (EE) cage (815×610×1,280 mm), equipped with horizontal and vertical boards, chains, swings, wooden blocks, and objects ...

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Abstract

The invention discloses methods and compositions useful for facilitating neuronal regeneration and functional recovery in neurodegenerative diseases. The methods and compositions utilize ligands for the sigma receptor, wherein the ligand is preferably siramesine, or salts, or solvates thereof. These molecules can be delivered alone or in combination with agents which treat or prevent neurodegenerative diseases such as those caused by ischemic stroke, diabetic peripheral neuropathy, cancer therapy induced neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Huntington's disease or Parkinson's disease. In other methods, the sigma receptor ligands are administered after stroke to facilitate functional recovery. The administration of the sigma receptor ligands effects faster functional recovery.

Description

FIELD OF THE INVENTION The present invention relates to methods of treatment to achieve neuronal regeneration in subjects with neurodegenerative disorders. In particular, the present invention relates to the use of sigma receptor ligands to facilitate neuronal regeneration and functional recovery in subjects after neurodegenerative disease. BACKGROUND OF THE INVENTION The existence of the sigma receptor was proposed by Martin et al. (1976) J. Pharmacol. Exp. Ther. 197: 517-532 to explain the psychotomimetic effects of benzomorphans. Initially, the sigma receptor was thought to be a novel opioid receptor. However, the binding of the benzomorphans to the sigma receptor is not antagonized by naloxone, the classic opioid receptor antagonist. Further, the benzomorphans bind to a site that is distinct from the phencyclidine receptor on the N-methyl-D-aspartate (NMDA) receptor complex. Thus, the sigma receptor is established as a unique receptor. The sigma receptor consists of two subty...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/00A61K31/195A61K31/438A61K31/473A61K31/485A61K31/495A61K38/17C07D295/096G06F21/00H04L29/06
CPCA61K31/00C07D295/096A61K31/495A61K31/438A61P3/10A61P9/10A61P21/02A61P25/00A61P25/02A61P25/14A61P25/16A61P25/28A61P43/00
Inventor OKSENBERG, DONNAURFER, ROMAN
Owner MS SCI CORP
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