Materials and methods for diagnosis, prevention and/or treatment of stress disorders and conditions associated with a-beta peptide aggregation
Inventors
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-11497739-B2
Publication Date
2022-11-15
Expiration Date
2029-09-24
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Abstract
The subject invention concerns materials and methods for treating and/or preventing diseases associated with accumulation of Aβ peptide in neural tissue. The subject invention also concerns materials and methods for treating and/or preventing stress disorders, such as post-traumatic stress disorder (PTSD). In one embodiment, a method of the invention comprises administering a therapeutically effective amount of cotinine, or a pharmaceutically acceptable salt thereof, to a person or animal in need of treatment. The methods of the invention can be used to prevent and/or treat Alzheimer's disease, Parkinson's disease, and/or Down's syndrome. The subject invention also concerns compositions that comprise cotinine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or adjuvant.The subject invention concerns materials and methods for detecting and diagnosing conditions associated with accumulation of Aβ peptide in neural tissue, such as Alzheimer's disease and Parkinson's disease, using the chemical cotinine. In one embodiment, the method comprises administering cotinine labeled with a detectable label to a person or animal. The presence of labeled cotinine in neural tissue is then determined. The level and/or location of cotinine can be analyzed and a diagnosis made. The subject invention also concerns cotinine labeled with a detectable label. In one embodiment, the cotinine is labeled with a radioisotope that can be detected by Positron Emission Tomography (PET) or single photon emission computed tomography (SPECT).
Core Innovation
The invention concerns materials and methods for treating and preventing diseases associated with the accumulation and aggregation of amyloid-beta (Aβ) peptide in neural tissue. A key embodiment features administering a therapeutically effective amount of cotinine, or a pharmaceutically acceptable salt thereof, to subjects in need of treatment. The methods apply to neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and cognitive impairments related to Down's syndrome.
Additionally, the invention addresses treatment and prevention of stress disorders, including post-traumatic stress disorder (PTSD), by administering cotinine or its pharmaceutically acceptable salts. The invention encompasses compositions comprising cotinine combined with pharmaceutically acceptable carriers.
The invention also discloses materials and methods for detecting and diagnosing conditions associated with Aβ accumulation in neural tissue by administering detectably labeled cotinine to a subject and determining its level or location in neural tissue. This enables in vivo diagnosis and monitoring utilizing modalities such as Positron Emission Tomography (PET) or single photon emission computed tomography (SPECT). Labeled cotinine can predict dementia related to Parkinson's disease by detecting its presence in striatum.
Claims Coverage
The patent contains one independent claim focused on a method of treating cognitive impairment in a subject having Down syndrome by administering cotinine or compositions thereof.
Method for treating cognitive impairment in Down syndrome
A method involving administering an effective amount of cotinine, or its isomer, racemate, or pharmaceutically acceptable salt, to a human or animal subject having Down syndrome to treat cognitive impairment, including memory loss.
Combination therapy with other drugs
The method optionally includes co-administration of one or more drugs for neurodegenerative conditions such as donepezil, galantamine, rivastigmine, memantine, rasagiline, selegiline, L-dopa, carbidopa, or benserazide, or drugs for stress disorders including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), MDMA, propranolol, clonidine, or ziprasidone.
Use of specific cotinine isomers
The cotinine administered can be racemic cotinine, or either the (−)-cotinine or (+)-cotinine isomer.
Target population specifications
The method specifically includes subjects who have not been diagnosed with Alzheimer's disease and may be less than 60 or less than 40 years of age.
Pharmaceutical composition concentration
The method involves administering a composition comprising cotinine in an amount ranging from about 1% to about 15% by weight of the total composition.
The claims principally cover a therapeutic method for cognitive impairment and memory loss in subjects with Down syndrome by administering cotinine or its derivatives, optionally in combination with other neurodegenerative or stress disorder drugs, specifying subject characteristics and pharmaceutical compositions.
Stated Advantages
Cotinine protects neurons against amyloid beta toxicity by inhibiting Aβ oligomerization.
Cotinine’s neuroprotective actions occur via mechanisms independent of nicotinic acetylcholine receptors.
Cotinine facilitates extinction of fear memories and decreases retention of fear, beneficial for stress disorders such as PTSD.
Cotinine enhances brain plasticity mechanisms by upregulating BDNF-stimulated phospho-CREB and Arc expression in cortical neurons.
Cotinine decreases anxiety induced by fear without affecting basal anxiety or motor coordination.
Cotinine can be labeled with radioisotopes for in vivo diagnosis and monitoring of Aβ accumulation using PET and SPECT imaging.
Documented Applications
Treatment and prevention of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and dementia associated with Down's syndrome.
Treatment and prevention of stress disorders such as post-traumatic stress disorder (PTSD).
Diagnostic and monitoring tools for conditions associated with Aβ peptide accumulation in neural tissue using labeled cotinine detected by PET or SPECT.
Use as a test agent to identify and evaluate efficacy of drugs for diseases associated with Aβ accumulation by monitoring changes in cotinine binding in neural tissue.
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