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Methods for therapeutic use of brain derived neurotrophic factor in the entorhinal cortex

a neurotrophic factor and entorhinal cortex technology, applied in the direction of drug compositions, peptide sources, peptide/protein ingredients, etc., can solve the problems that no existing therapy for ad and other neurodegenerative conditions specifically targets neurodegeneration, aav and hsv, and can produce toxicity and/or immunogenicity

Inactive Publication Date: 2003-07-03
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] In another variation of this embodiment, measured cognitive function in treated animals improves to a level equivalent to function in unimpaired animals.
[0013] Practice of the invention enables one to improve cognitive function lost to neurodegeneration in the EC. The effects of the inventive method can extend to trkB receptor containing tissues other than the EC, such as the HC and the frontal, parietal and visual cortices, thereby offering the opportunity to substantially reverse the effects of neurodegeneration associated with disease (such as Alzheimer's) or aging.

Problems solved by technology

Yet no existing therapy for AD and other neurodegenerative conditions specifically targets neurodegeneration in the EC for treatment.
However, some of these viruses (e.g., AAV and HSV) can produce toxicity and / or immunogenicity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example ii

Pre- and Post-Operative Water Maze Testing

[0044] Water maze apparatus: The first run of water maze testing was conducted in a black circular tank (diameter: 1.40 m; height: 0.60 m) filled with water (19-21.degree. C.). A black escape platform was submerged 3 cm below the surface of the water in a specific location during training / acquisition trials. The escape platform was removed during probe testing. To provide a clear visible cue, four wooden posts were attached to the platform during cued trials. Black curtains were hung around the tank and four unique wall cues were hung to serve as environmental landmarks. For data analysis, the tank was divided into four quadrants: north, south, east, and west. Both collection and analysis of the data were performed using a San Diego Instruments (San Diego, Calif.) computer tracking system.

[0045] Subsequent water maze testing was conducted in a white circular tank (diameter: 1.83 m; height: 0.70 m) filled with water made opaque by the additio...

example iii

BDNF Localization in the EC

[0052] To determine the extent to which exogenous BDNF was retained at the infusion site in treated animals, hypothalamus, hippocampus, entorhinal cortex, prefrontal cortex, and the remainder of neocortex were sectioned from anesthesized animals, then immediately dissected and frozen in liquid nitrogen. Tissues were stored at -80.degree. C.

[0053] Immunohistochemistry for BDNF was performed using a rabbit anti-BDNF antibody at a concentration of 1:6000 and sections prepared from the treated animals. Specificity of the antibodies was verified by omitting the primary antibody with a resultant loss of cellular labeling.

[0054] Levels of BDNF were determined using two-site enzyme-linked immunosorbent assays (ELISA) developed according to standard procedures (Conner et al., J. Neurosci, 17:2295, 1997). The assay was specific for BDNF and was relatively linear over the range for which it was used (1-100 pg / sample). Assays developed for BDNF showed no detectable cr...

example iv

Effect of BDNF Treatment on Expression of BDNF Sensitive Receptors

[0058] Total RNA was isolated from tissues by using the RNA Extraction Kit (Pharmacia-Biotech), and double-stranded DNA was synthesized from 1-5 .mu.g of total RNA. Biotin-labeled cRNA was purified, fragmented, and hybridized to the Affymetrix Rat arrays in 100 mM Mes, pH 7.4 / 1 M NaCl / 20 mM EDTA / 0.01% Tween 20. The arrays were washed and stained with streptavidin-phycoerythrin and then scanned with an Affymetrix GeneArray Scanner. Data were analyzed with the Affymetrix Genechip Expression Analysis software (version 3.1).

[0059] The arrays were analyzed using a library containing probe sets for approximately 10,000 known genes and ESTs. A summary of the number and direction of changes between groups can be found in Table 1, below. Of those, 10 were chosen to verify by RT-PCR for the entorhinal cortex, as listed in Table 2. Complete listings of the gene changes (not including ESTs) comparing BDNF-infused aged animals (n=...

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Abstract

A protocol for use of growth factors to stimulate neuronal cell growth and activity in trkB receptor containing cortical tissues, including the entorhinal and hippocampal cortices. The method introduces exogenous growth factor, such as BDNF, NT-4 / 5 and NT-3, into the EC. The method is useful in therapy of defective, diseased and damaged neurons in the mammalian brain, of particular usefulness for treatment of neurodegenerative conditions such as Alzheimer's disease or for normal aging.

Description

[0001] The invention relates to methods for treatment of neurodegenerative disease and aging, and methods for delivery of therapeutic growth factor into the mammalian brain. Specifically, the invention pertains to the use of growth factors that activate the trkB nervous system growth factor receptor (including brain-derived neurotrophic factor (BDNF) and nervous system growth factor-4 / 5 (NT-4 / 5)) to stimulate neuronal activity in the entorhinal cortex (EC).HISTORY OF THE RELATED ART[0002] Neurodegeneration in Alzheimer's disease begins within the hippocampus and entorhinal cortex. In patients with even the mildest level of clinical dementia, a 30% loss of EC layer II neurons is observed. By the onset of severe AD, the loss has risen to 90%. Yet no existing therapy for AD and other neurodegenerative conditions specifically targets neurodegeneration in the EC for treatment.[0003] BDNF and NT-4 / 5 are neuronal growth factors which play a role in brain function through a variety of mecha...

Claims

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Application Information

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IPC IPC(8): A61K38/18A61P25/00A61K38/22A61P25/28
CPCA61K38/185A61P25/00A61P25/28
Inventor TUSZYNSKI, MARK H.
Owner RGT UNIV OF CALIFORNIA
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