Neuroprotective peptides

a neuroprotective and peptide technology, applied in the direction of peptides/protein ingredients, drug compositions, peptides, etc., can solve the problems of neuronal cell death via acute and delayed damage processing, many potential neuroprotective agents many cpps also exhibit toxicity at low to moderate doses, etc., to reduce cell death and inhibit or ameliorate neurodamaging events/pathways. , the effect of reducing

Inactive Publication Date: 2016-09-01
UNIV OF WESTERN AUSTRALIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0086]These findings demonstrate that the peptides of the invention have the ability to, and can be used in methods to, inhibit or ameliorate neurodamaging events/pathways associated with excitotoxic and ischemic injuries. Also, as shown by the effects of protamine and protamine derivatives in pre-insult exposure trials contained herein, a new key finding was that protamine treatment

Problems solved by technology

While the exact mechanisms of TAT's neuroprotective action are not fully understood, there is speculation that it interferes with NMDA receptor activation (Xu et al.
Increased extracellular levels of the neurotransmitter glutamate can

Method used

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Examples

Experimental program
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Effect test

experimental example 4

Animal Trial

[0233]In an initial animal trial that was conducted, it was shown that Arg-9 (R9), R18 and protamine (Ptm) possessed neuroprotective activity in vivo. These trials showed the efficacy of R9D peptide in rat permanent middle cerebral artery occlusion (MCAO) stroke model. R9D peptide was administered intravenously 30 min post-MCAO. Infarct volume (brain injury) was measured 24 h post-MCAO (mean±SEM). This is shown in FIGS. 5 and 27 where it can be seen that (Ns=812 animals for each group) treatment with R9D, R18 and protamine (Ptm) showed a statistically significant neuroprotective effect by reducing infarct volume (brain damage) by approximately 20% after a MCAO stroke.

General Observations and Discussion

[0234]The Applicant assessed TAT as known neuroprotective example and three other CPPs (penetratin, R9, and Pep-1) for their neuroprotective properties in cortical neuronal cultures following exposure to glutamic acid, kainic acid, or in vitro ischemia (oxygen-glucose depri...

experimental example 1

Neuroprotection Following Glutamic Acid Exposure

[0255]Protamine sulphate (protamine; Ptm) provided significant neuroprotection in a dose response manner (FIGS. 9, 10, 12, 13, 15). Visual assessment of cultures post-injury also confirmed the neuroprotective effect that ranged from for untreated glutamic acid exposed cultures to 85-100%% survival for protamine treated cultures. In addition, a 5 or 10 minute protamine pre-exposure was also highly neuroprotective resulting 100% neuronal survival (FIG. 11). In dose response experiments, low molecular weight (LMWP), protamine 1 (Ptm1), protamine 2 (Ptm2), protamine 3 (Ptm3), protamine 4 (Ptm4), protamine 5 (Ptm5), peptide were also neuroprotective (FIGS. 12, 13, 15).

[0256]In protamine and LMWP pre-exposure experiments, protamine was neuroprotective when neurons where exposed to protamine immediately before and 1 or 2 hours prior to glutamic acid insult, while LMWP was only neuroprotective when exposure was immediately before glutamic acid...

experimental example 2

Neuroprotection Following Oxygen-Glucose Deprivation (OGD)

[0257]In the OGD model protamine was neuroprotective when neurons were treated with peptide 1 hour before insult (FIG. 18) or post-insult (FIG. 16, 17) In addition, when added for 15 or 30 minutes, post-OGD protamine was also neuroprotective (FIGS. 19, 20, 21, 22), LMWP was not neuroprotective when neurons were pre-exposed to the peptide 1 hour before OGD, but it was neuroprotective when added for 15 minutes post-OGD. In addition when protamine peptides (Ptm1-Ptm5) and LMWP were added for 15 minutes post-OGD, peptides Ptm2, Ptm4, Ptm5 and LMWP were neuroprotective (FIG. 22).

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Abstract

The invention relates to the use of an isolated peptide of 10 to 32 amino acid residues in length for the treatment of neural injury, wherein the isolated peptide comprises at least 10 to 22 arginine residues. The peptide may be a poly-arg sequence or an arginine-rich peptide.

Description

FIELD OF THE INVENTION[0001]This invention relates to peptides having neuroprotective activity, the peptides being useful in treating stroke and other neural injuries or disorders. The invention relates further to a method of treating a neural injury or disorder using the peptides of the invention.BACKGROUND OF THE INVENTION[0002]Cell penetrating peptides (CPPs) are small peptides that are used to facilitate the delivery of normally non-permeable cargos such as other peptides, proteins, nucleic acids or drugs into cells.[0003]The development of cell penetrating peptides (CPPs), also referred to as peptide transduction domains (PTDs), as facilitators of therapeutic drug delivery has progressed significantly since the initial discovery of a PTD within the human immunodeficiency virus-type 1 trans-activating transcriptional activator (Frankel and Pabo, 1988; Green and Loewenstein, 1988), commonly referred to as TAT. Since then, the active transporting portion of this sequence has been ...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K9/00
CPCA61K9/0053A61K38/1709C07K7/06C07K7/08C07K14/001A61K38/00A61P15/00A61P21/00A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P43/00A61P9/10
Inventor MELONI, BRUNO
Owner UNIV OF WESTERN AUSTRALIA
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