Methods of treating and preventing diseases and disorders of the central nervous system
Inventors
McGavern, Dorian B. • Roth, Theodore
Assignees
US Department of Health and Human Services
Publication Number
US-9308163-B2
Publication Date
2016-04-12
Expiration Date
2033-02-05
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Abstract
Disclosed is a method of treating or preventing a disease or disorder of the central nervous system (CNS) in a patient comprising administering transcranially, for example, directly to the skull, an effective amount of an anti-inflammatory agent to the patient. Examples of the anti-inflammatory agent include glutathione and inhibitors of purinergic receptors such as P2X4, P2X7, P2Y6, and P2Y12 receptors. Examples of disease or disorder of the CNS include brain injury, particularly traumatic brain injury, inflammation, infection, degeneration of brain cells, stroke, brain edema, tumor, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Also disclosed is a kit comprising at least one anti-inflammatory agent and printed materials containing instructions for transcranially administering the anti-inflammatory agent to the patient having a disease or disorder of the CNS, disorder of the CNS.
Core Innovation
The invention provides a method of treating or preventing diseases or disorders of the central nervous system (CNS) by administering transcranially an effective amount of an anti-inflammatory agent or reactive oxygen scavenger to a patient. This method bypasses the blood brain barrier (BBB) by delivering therapeutic agents directly through the skull, achieving a high local concentration rapidly at the site of CNS injury or inflammation.
The method addresses the problem that many drugs targeting neuroprotection after CNS injury, particularly traumatic brain injury (TBI), have proven ineffective due to the BBB blocking systemic drugs from reaching the CNS in adequate concentrations. Diseases or disorders targeted include brain injury, inflammation, infection, degeneration of brain cells, stroke, brain edema, tumor, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. The CNS injuries can involve complex cascades of damage including inflammatory immune responses and excitotoxicity that lead to neuronal loss.
The invention further details that the transcranial administration can inhibit or reduce formation of reactive microglia, limit recruitment of neutrophils and monocytes, and reduce dead cell numbers in brain parenchyma or meninges after TBI. Anti-inflammatory agents include glutathione and purinergic receptor inhibitors targeting P2X4, P2X7, P2Y6, and P2Y12 receptors. The invention also provides a kit comprising an anti-inflammatory agent and instructions for transcranial administration.
Claims Coverage
The patent includes one independent claim focused on a method of transcranially treating a CNS disease or disorder using an anti-inflammatory agent.
Transcranial administration of anti-inflammatory agent for CNS diseases
A method of treating a disease or disorder of the central nervous system by administering transcranially an effective amount of an anti-inflammatory agent in an aqueous vehicle, where administration includes direct application to the skull, application through the scalp, or injection into the skull bone.
Specific diseases and agents targeted for treatment
The method specifically treats traumatic brain injury, brain inflammation, or stroke using anti-inflammatory agents comprising glutathione or purinergic receptor inhibitors selected from trinitrophenyl-ATP hydrate, oxidized ATP, N,N''-1,4-butanediylbis[N'-3-isothiocyanatophenyl)]thiourea, and MeSAMP.
Administration modes and sites
The transcranial administration can be performed via a transdermal patch, subcutaneous injection under the scalp, or injection into the cancellous bone of the skull.
The claims cover transcranial administration of specific anti-inflammatory agents to treat CNS disorders, focusing on methods bypassing the BBB via skull or scalp application, and covering both agent selection and modes of administration.
Stated Advantages
Effective delivery of therapeutic agents bypassing the blood brain barrier to rapidly reach CNS injury sites with high local concentrations.
Reduction or inhibition of reactive microglia formation, neutrophil and monocyte recruitment, and cell death in brain parenchyma or meninges following CNS injury.
Use of low molecular weight compounds allowing efficient diffusion through the porous skull layers for improved CNS treatment.
Documented Applications
Treatment or prevention of central nervous system diseases or disorders including traumatic brain injury, brain inflammation, stroke, infection, brain edema, tumor, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
Inhibition or reduction of reactive microglia formation, neutrophil and monocyte recruitment, and reduction of dead cells in brain tissues after traumatic brain injury arising from activities such as boxing, football, soccer, hockey, armed conflict, or brain surgery.
Use in clinical assessment contexts employing imaging and cognitive testing to monitor CNS injury and treatment efficacy.
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