Burke Neurological Institute

Cornell University

Neuronasal, Inc.

Cornell Research Foundation Inc.

The City University of New York

Beth Israel Deaconess Medical Center, Inc.

University of Vermont and State Agricultural College

Rajiv R Ratan

Saravanan Karuppagounder

Thomas I Bradshaw

Marie T Filbin

Ishraq Alim, I

Irina Gazaryan

Natalya Smirnova

Douglas A Greene

Ching-Hwa Sung

Jen-Zen Chuang

Brett C Langley

Juan Chavez

Brian S Ko

Robert Hondal

Ambreena Siddiq

Saravanan S Karuppagounder

The present disclosure describes methods of administering N-acetylcysteine (NAC) via intranasal nose-to-brain administration. The effect of intranasal NAC nose-to-brain administration can be monitored using an analytical technique, for example, magnetic resonance spectroscopy (MRS). In some embodiments, intranasal nose-to-brain NAC can be used to treat a condition, for example, a brain injury.

Methods of treating brain disorders

The present disclosure describes methods of treating a central nervous system condition associated with oxidative stress using a 5-lipoxigenase activating protein (FLAP) inhibitor, for example, N-acetylcysteine or nordihydroguaiaretic acid. The present disclosure also describes methods of treating a central nervous system condition with N-acetylcysteine and a second therapeutic agent such as prostaglandin E2.

Use of N-acetylcysteine to treat central nervous system disorders

This invention relates to methods of administering compounds containing selenium, selenocysteine, or a selenocysteine peptide to treat, for example, conditions associated with selenium deficiency, or ferroptoptic, parthanototic, and endoplasmic reticulum stress, and/or cancer. The methods of treatment may activate or inhibit (via TFAP2C and Sp1 proteins) the adaptive homeostatic response of the selenome. The compounds may contain a targeting sequence that causes them to be delivered to specific organs and/or tissues. The compounds may be administered, for example, orally, intranasally, intravenously, or by a minimally invasive catheter or BrainPath.

Methods of treatment comprising Selenoprotein P fragment-containing compounds

The present disclosure describes methods of treating a central nervous system condition associated with oxidative stress using a 5-lipoxigenase activating protein (FLAP) inhibitor, for example, N-acetylcysteine or nordihydroguaiaretic acid. The present disclosure also describes methods of treating a central nervous system condition with N-acetylcysteine and a second therapeutic agent such as prostaglandin E.

Selenium-based therapies

Methods for treating a patient suffering from neural cell injury, the method comprising administering to the patient an effective amount of a HIF prolyl-4-hydroxylase inhibiting compound having the following general formula (1) wherein Ris a cyclic group containing at least three and up to seven carbon atoms and optionally containing one or more heteroatoms selected from O, N, and S, and optionally attached to the shown carbon atom by a linking group; Ris independently selected from said cyclic groups of Rand acyclic hydrocarbon groups Rcontaining up to twenty carbon atoms; Ris selected from hydrogen atom and hydrocarbon groups containing up to six carbon atoms; Rand Rare independently selected from hydrogen atom, hydrocarbon groups containing up to three carbon atoms, halogen atom, and polar groups, as well as methylene-linked versions thereof; and t is 0 or 1.

Prolylhydroxylase/ATF4 inhibitors and methods of use for treating neural cell injury or death and conditions resulting therefrom

The present invention relates to methods for enhancing Hypoxia inducible factor-1 (HIF) activity in a cell by contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analog R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide.

Compounds for enhancing hypoxia inducible factor activity and methods of use

Compounds for inhibiting hypoxia inducible factor (HIF) prolyl-4-hydroxylases (PHDs) having the general formula (1). Methods of using these and related compounds for treating a patient having a condition that would benefit from inhibiting HIF PHD are also described herein.

Prolylhydroxylase inhibitors and methods of use

The present invention relates to a method for enhancing arginase activity in a damaged or injured cell. In other aspects, the invention provides a method for treating a disorder that can be treated by enhancing arginase activity in a human in need thereof, the method comprising administering to the human an effective amount of a compound that enhances arginase activity. Such disorders include ischemia, hypoxia, neurodegenerative disease or condition, stroke or trauma of the nervous system. In yet another aspect, the invention provides methods for promoting regeneration of a neural cell in a human in need thereof.

Compounds for enhancing arginase activity and methods of using same

The NF-E2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant defense and detoxification. To directly monitor stabilization of Nrf2 we fused its Neh2 domain, responsible for the interaction with its nucleocytoplasmic regulator, Keap1, to firefly luciferase (Neh2-luciferase). It is shown herein that Neh2 domain is sufficient for recognition, ubiquitination and proteasomal degradation of Neh2-luciferase fusion protein. The novel Neh2-luc reporter system allows direct monitoring of the adaptive response to redox stress and classification of drugs based on the time-course of reporter activation. The novel reporter was used to screen a library of compounds to identify activators of Nrf2. The most robust and yet non toxic Nrf2 activators found&#x2014;nordihydroguaiaretic acid, fisetin, and gedunin-induced astrocyte-dependent neuroprotection from oxidative stress via an Nrf2-dependent mechanism.

Reporter system for high throughput screening of compounds and uses thereof

In one aspect, the invention relates to a method for identifying a drug candidate with activity as a neuroprotective agent. The method includes determining whether a compound reduces ATF4 activity; and identifying the compound that reduces ATF4 activity as a drug candidate.

ATF4 inhibitors and their use for neural protection, repair, regeneration, and plasticity

The present invention relates to a method for identifying a drug candidate for enhancing expression of p21cip1/waf1 in a human patient suffering from a medical condition that can be treated by enhancing expression of p21C&#x3c6;1/waf1. The method includes (a) providing a cell line comprising a nucleic acid sequence that comprises a p21cip1/waf1 promoter operationally ligated to a reporter domain; (b) exposing the cell line to a compound; and (c) identifying a compound that induces expression of the reporter domain. The compound that induces expression of the reporter domain is a drug candidate for treating a medical condition that can be treated by enhancing expression of p21cip1/waf1.

Compounds for enhancing p21 expression and methods of use thereof

This invention relates to the novel identification of arginase as an enzymatic activity which can reverse inhibition of neuronal regeneration in the central and peripheral nervous system. Assays to monitor the effects of various agents on arginase expression and thus on neuronal regeneration and repair and to identify agents which will block or promote the inhibitory effects on neuronal outgrowth are provided. This invention also relates to compositions and methods using agents that can reverse the inhibitory effects of myelin on neural regeneration by affecting arginase activity or putrescine and derivative polyamine levels in a neuron. Methods for regulating and for promoting (or repressing) neuronal growth or regeneration in the nervous system, methods for treating injuries or damage to nervous tissue or neurons, and methods for treating neural degeneration associated with conditions, disorders or diseases, comprising the step of administering at least one of the compositions according to this invention, are provided.

Methods for stimulating nervous system regeneration and repair by regulating arginase I and polyamine synthesis

A method of stimulating neurite outgrowth in a subject may include administering to the subject a formulation that includes a tctex-1-related polypeptide that stimulates neurite outgrowth in vitro.

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Scarsdale, NY, United States of America

Rajiv R Ratan