The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids

The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous s...

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Vydáno v:Journal of internal medicine Ročník 294; číslo 3; s. 281 - 294
Hlavní autoři: Bäckström, Torbjörn, Turkmen, Sahruh, Das, Roshni, Doverskog, Magnus, Blackburn, Thomas P.
Médium: Journal Article
Jazyk:angličtina
Vydáno: England Blackwell Publishing Ltd 01.09.2023
Témata:
Acetic acid
Aged
allopregnanolone
Alzheimer Disease - drug therapy
Alzheimer's disease
Animal cognition
Animals
Central nervous system
Cognition
Cognitive ability
Cognitive Dysfunction - drug therapy
dementia
Dementia disorders
GABA-A receptor
gamma-Aminobutyric Acid - pharmacology
Hepatic encephalopathy
Humans
Impairment
Medroxyprogesterone acetate
Memory
Neurodegenerative diseases
Neurosteroids
Neurosteroids - therapeutic use
Pregnanolone
Pregnanolone - pharmacology
Receptors
Receptors, GABA-A
Steroid hormones
Steroids
Transgenic animals
γ-Aminobutyric acid
dementia
allopregnanolone
memory
GABA-A receptor
neurosteroids
ISSN:0954-6820, 1365-2796, 1365-2796
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Abstract The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA‐A receptor modulating stress and sex steroids (steroid‐PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA‐A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid‐PAMs and opportunities to treat these adverse effects of steroid‐PAMs with novel GAMSAs.
AbstractList The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.
The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.
Author Turkmen, Sahruh
Bäckström, Torbjörn
Doverskog, Magnus
Das, Roshni
Blackburn, Thomas P.
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  fullname: Bäckström, Torbjörn
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  organization: University of Umeå
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  surname: Turkmen
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  surname: Das
  fullname: Das, Roshni
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  organization: Umecrine Cognition AB
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  givenname: Thomas P.
  surname: Blackburn
  fullname: Blackburn, Thomas P.
  organization: Umecrine Cognition AB
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-212756$$DView record from Swedish Publication Index (Umeå universitet)
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Keywords dementia
allopregnanolone
memory
GABA-A receptor
neurosteroids
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2017; 69
1986; 232
2005; 512
2004; 46
2000; 73
2019; 226
2019; 108
2002; 934
2011; 6
2012; 31
2022; 234
1999; 868
2017; 50
1987; 61
2023; 151
2009; 72
2002; 67
2010; 334
2006; 49
1995; 705
2000; 75
2018; 235
2022; 12
2005; 6
2006; 186
2001; 37
2005; 93
1994; 17
2003; 982
1990; 4
2012; 60
1993; 607
1990; 11
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2010; 57
1990; 15
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1992; 447
1992; 13
2008; 4
1991; 159
2000; 290
2016; 78
2010; 67
2009; 56
2014; 5
2013; 14
2013; 10
2000; 169
1991; 42
2002; 43
2003; 2
2005; 30
2016; 233
1999; 96
1998; 50
2014; 9
2011; 162
2008; 60
1996; 9
1968; 11
2007; 27
1987; 241
1967; 81
2011; 218
2019; 76
2016; 54
2020; 349
1994; 46
2022; 48
2017; 174
1995; 19
2018; 66
2009; 136
1986; 319
2014; 113
1987; 131
1997; 764
1987; 20
2022; 141
2022; 2022
2013; 38
2018; 392
2004; 19
2013; 34
2023; 233
2017; 13
2013; 536
2021; 19
2002; 22
2010; 133
2006; 143
2012; 8
2010; 93
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Snippet The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging...
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SubjectTerms Acetic acid
Aged
allopregnanolone
Alzheimer Disease - drug therapy
Alzheimer's disease
Animal cognition
Animals
Central nervous system
Cognition
Cognitive ability
Cognitive Dysfunction - drug therapy
dementia
Dementia disorders
GABA-A receptor
gamma-Aminobutyric Acid - pharmacology
Hepatic encephalopathy
Humans
Impairment
Medroxyprogesterone acetate
Memory
Neurodegenerative diseases
Neurosteroids
Neurosteroids - therapeutic use
Pregnanolone
Pregnanolone - pharmacology
Receptors
Receptors, GABA-A
Steroid hormones
Steroids
Transgenic animals
γ-Aminobutyric acid
Title The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fjoim.13705
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Volume 294
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