Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism
ObjectiveAllopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both...
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| Format: | Article |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1286931/full |
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| author | Tian Wang Tian Wang Shuhua Chen Zisu Mao Yuan Shang Roberta Diaz Brinton Roberta Diaz Brinton Roberta Diaz Brinton |
| author_facet | Tian Wang Tian Wang Shuhua Chen Zisu Mao Yuan Shang Roberta Diaz Brinton Roberta Diaz Brinton Roberta Diaz Brinton |
| author_sort | Tian Wang |
| collection | DOAJ |
| description | ObjectiveAllopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer’s disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways.MethodsMechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses.ResultsIn hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca2+/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABAA and L-type Ca2+ channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABAA and L-type Ca2+ channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics.ConclusionCollectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain. |
| first_indexed | 2024-03-08T21:13:46Z |
| format | Article |
| id | doaj.art-d75664ddf42348dfa48a983e4f31e722 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-08T21:13:46Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-d75664ddf42348dfa48a983e4f31e7222023-12-22T04:32:54ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-12-011410.3389/fendo.2023.12869311286931Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanismTian Wang0Tian Wang1Shuhua Chen2Zisu Mao3Yuan Shang4Roberta Diaz Brinton5Roberta Diaz Brinton6Roberta Diaz Brinton7Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, United StatesDepartment of Neurology, College of Medicine Tucson, University of Arizona, Tucson, AZ, United StatesCenter for Innovation in Brain Science, University of Arizona, Tucson, AZ, United StatesCenter for Innovation in Brain Science, University of Arizona, Tucson, AZ, United StatesCenter for Innovation in Brain Science, University of Arizona, Tucson, AZ, United StatesCenter for Innovation in Brain Science, University of Arizona, Tucson, AZ, United StatesDepartment of Neurology, College of Medicine Tucson, University of Arizona, Tucson, AZ, United StatesDepartment of Pharmacology, College of Medicine Tucson, University of Arizona, Tucson, AZ, United StatesObjectiveAllopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer’s disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways.MethodsMechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses.ResultsIn hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca2+/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABAA and L-type Ca2+ channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABAA and L-type Ca2+ channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics.ConclusionCollectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain.https://www.frontiersin.org/articles/10.3389/fendo.2023.1286931/fullallopregnanolonecalcium signalingmitochondrianeuroplasticityastrocytic function |
| spellingShingle | Tian Wang Tian Wang Shuhua Chen Zisu Mao Yuan Shang Roberta Diaz Brinton Roberta Diaz Brinton Roberta Diaz Brinton Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism Frontiers in Endocrinology allopregnanolone calcium signaling mitochondria neuroplasticity astrocytic function |
| title | Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism |
| title_full | Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism |
| title_fullStr | Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism |
| title_full_unstemmed | Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism |
| title_short | Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism |
| title_sort | allopregnanolone pleiotropic action in neurons and astrocytes calcium signaling as a unifying mechanism |
| topic | allopregnanolone calcium signaling mitochondria neuroplasticity astrocytic function |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1286931/full |
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