Abstract: The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

Abstract: The application provides data from a clinical trial of a PSD-95 inhibitor in subjects undergoing endovascular repair of an aneurysm in or otherwise affecting the CNS. The subjects were stratified by whether the aneurysm ruptured before performing the endovascular surgery. Rupture is associated with higher mortality or increased debilitation if a subject survives. The trial provided evidence of significant benefit in subjects with and without aneurysm rupture before endovascular was surgery performed. Surprisingly, the subjects benefitting most from treatment as judged both by pathology and neurocognitive outcome were those in which the aneurysm had ruptured causing a subarachnoid hemorrhage. These data constitute evidence that a PSD-95 inhibitor is beneficial not only in ischemic and hemorrhagic stroke but in forms of hemorrhage in or affecting the CNS, particularly, subarachnoid hemorrhage.

Abstract: The invention provides agents useful for treating pain. An exemplary agent comprises or consists of the a portion of a retroviral Tat protein. One such agent is the peptide Tat-NR2B9c. This peptide has previously been described as an agent for inhibiting damaging effects of stroke and similar conditions via inhibition of PSD95 interactions with NMDA receptors and/or NOS. The present application provides data showing that the Tat-NR2B9c peptides is effective in alleviation of pain. The alleviation of pain can be obtained at a dose of the peptide below the dose required to inhibit PSD-95 interactions with NMDAR or NOS.

Abstract: This invention relates to compounds that modulate TRPM7 protein activity and use of the same for treatment or prophylaxis of ischemia, cancer, pain or glaucoma.

Abstract: The application provides data from a clinical trial of a PSD-95 inhibitor in subjects undergoing endovascular repair of an aneurysm in or otherwise affecting the CNS. The subjects were stratified by whether the aneurysm ruptured before performing the endovascular surgery. Rupture is associated with higher mortality or increased debilitation if a subject survives. The trial provided evidence of significant benefit in subjects with and without aneurysm rupture before endovascular was surgery performed. Surprisingly, the subjects benefiting most from treatment as judged both by pathology and neurocognitive outcome were those in which the aneurysm had ruptured causing a subarachnoid hemorrhage. These data constitute evidence that a PSD-95 inhibitor is beneficial not only in ischemic and hemorrhagic stroke but in forms of hemorrhage in or affecting the CNS, particularly, subarachnoid hemorrhage.

Abstract: The invention provides methods of treating a patient having epilepsy in which an effective regime of an agent that inhibits specific binding of PSD-95 to an NMDA receptor is administered to a patient.

Abstract: The invention provides animal models and clinical trials for assessing agents for potential use in treating and effecting prophylaxis stroke and other neurological diseases, particularly those mediated at least in part by excitoxitity. The invention also provides preferred dosage and infusion regimes and pharmaceutical compositions for clinical application of such agents.

Abstract: A method of inhibiting the binding between N-methyl-D-aspartate receptors and neuronal proteins in a neuron is disclosed. The method comprises administering to the neuron an effective inhibiting amount of a peptide replacement agent for the NMDA receptor or neuronal protein interaction domain that effect said inhibition of the NMDA receptor-neuronal protein interaction. The method is of value in reducing the damaging effect of injury to mammalian cells. Postsynaptic density-95 protein (PSD-95) couples neuronal N-methyl-D-aspartate receptors (NMDARs) to pathways mediating excitotoxicity, ischemic and traumatic brain damage. This coupling was disrupted by transducing neurons with peptides that bind to modular domains on either side of the PSD-95NMDAR interaction complex.

Abstract: The invention is based in part on identifying a core region of ND2 responsible for interacting with Src to within residues 289-321 of ND2 and more particularly residues 307-321 or 310-321 of ND2. Peptides including, overlapping or from within this region can be used to inhibit ND2 interaction with Src Inhibition of this interaction is useful for treatment or prophylaxis of neurological diseases and disorders, pain and cancer.

Abstract: The invention provides methods for treating stroke and compositions for use in the same. The methods employ a chimeric peptide of an active peptide and an internalization peptide. The internalization peptide is a tat variant that promotes uptake of itself and a linked active peptide into a cell without substantial binding to N-type calcium channels. Use of the tat variant allows treating of stroke free of certain side effects associated with binding to N-type calcium channels. Tat variant peptides can also be linked to other active agent for use in treating other diseases.

Abstract: The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

Abstract: The invention provides animal models and clinical trials for assessing agents for potential use in treating and effecting prophylaxis stroke and other neurological diseases, particularly those mediated at least in part by excitoxitity. The invention also provides preferred dosage and infusion regimes and pharmaceutical compositions for clinical application of such agents.

Abstract: The invention provides agents useful for treating pain. An exemplary agent comprises or consists of the a portion of a retroviral Tat protein. One such agent is the peptide Tat-NR2B9c. This peptide has previously been described as an agent for inhibiting damaging effects of stroke and similar conditions via inhibition of PSD95 interactions with NMDA receptors and/or NOS. The present application provides data showing that the Tat-NR2B9c peptides is effective in alleviation of pain. The alleviation of pain can be obtained at a dose of the peptide below the dose required to inhibit PSD-95 interactions with NMDAR or NOS.

Abstract: The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

Abstract: The invention is based in part on identifying a core region of ND2 responsible for interacting with Src to within residues 289-321 of ND2 and more particularly residues 307-321 or 310-321 of ND2. Peptides including, overlapping or from within this region can be used to inhibit ND2 interaction with Src Inhibition of this interaction is useful for treatment or prophylaxis of neurological diseases and disorders, pain and cancer.

Abstract: The invention provides a combination treatment for ischemia conditions in or otherwise affecting the CNS, such as stroke. The treatment invoices administration of a PSD-95 inhibitor and performing reperfusion therapy (e.g. by administration of tPA). Administration a PSD-95 inhibitor in combination with reperfusion therapy increases the efficacy of the reperfusion therapy and/or slows the decline in efficacy of reperfusion therapy with time after onset of ischemia thus extending the window in which reperfusion therapy can be administered.

Abstract: This invention relates to methods of screening for modulators of mammalian cell injury cause by TRPM7 gene and protein activity, compounds that modulate TRPM7 gene and protein activity and methods of treatment of mammalian cell injury using modulators of TRPM7 gene and protein activity.

Abstract: This invention relates to compounds that modulate TRPM7 protein activity and use of the same for treatment or prophylaxis of ischemia, cancer, pain or glaucoma.

Abstract: The invention provides agents useful for treating pain. An exemplary agent comprises or consists of the a portion of a retroviral Tat protein. One such agent is the peptide Tat-NR2B9c. This peptide has previously been described as an agent for inhibiting damaging effects of stroke and similar conditions via inhibition of PSD95 interactions with NMDA receptors and/or NOS. The present application provides data showing that the Tat-NR2B9c peptides is effective in alleviation of pain. The alleviation of pain can be obtained at a dose of the peptide below the dose required to inhibit PSD-95 interactions with NMDAR or NOS.

Abstract: The invention provides methods of treating stroke and related conditions exacerbated by fever and/or hyperglycemia by administering peptides or peptidomimetics that inhibit binding of NMDAR 2B to PSD-95 to a patient.