Allopregnanolone Pleiotropic Action in Neurons and Astrocytes: Calcium Signaling Pathways as the Unifying Mechanism
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE229627 | GEO | 2023/12/22
REPOSITORIES: GEO
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Project 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.
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Project description:Allopregnanolone Pleiotropic Action in Neurons and Astrocytes: Calcium Signaling Pathways as the Unifying Mechanism
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Project description:We report the application of RNA-seq for molecular profiling of cultured, cortical astrocytes. Our data set is based on about 40 million unique reads per sample in four independent mRNA preparations. Cortical astrocytes are a prototypical cell model for investigating calcium signaling. For analysis of calcium fluxes, we performed direct calcium imaging in the endoplasmic reticulum and in the cytosol. We describe in our study the physiological profile of homeostatic and agonist-induced calcium fluxes. Furthermore, we show how ER calcium release shapes the cytosolic calcium signal. This transcriptome dataset was used to profile the calcium toolkit of astrocytes. The data suggest that a small number of calcium signaling-related proteins mediate calcium homeostasis in astrocytes.
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Project description:For several years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone) may have therapeutic potential for treatment of various stress-related diseases including post-traumatic stress disorder (PTSD), depression, alcohol use disorders (AUDs), as well as neurological and psychiatric conditions that are worsened in the presence of stress, such as multiple sclerosis, schizophrenia, and seizure disorders. In this review, we make the argument that the pleiotropic actions of allopregnanolone account for its ability to promote recovery in such a wide variety of illnesses. Likewise, the allopregnanolone precursors, pregnenolone and progesterone, share many actions of allopregnanolone. Of course, pregnenolone and progesterone lack direct effects on GABAA receptors, but these compounds are converted to allopregnanolone in vivo. This review presents a theoretical framework for understanding how endogenous neurosteroids that regulate 1) γ-aminobutyric acid (GABA)A receptors, 2) corticotropin releasing factor (CRF) and 3) pro-inflammatory signaling in the innate immune system and brain could play a key role in both the prevention and treatment of stress-related disease. We further discuss cautions and limitations of allopregnanolone or precursor therapy as well as the need for more clinical studies.
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Project description:There is an integral relationship between vascular cells and leukocytes in supporting healthy tissue homeostasis. Furthermore, activation of these two cellular components is key for tissue repair following injury. Toll-like receptors (TLRs) play a role in innate immunity defending the organism against infection, but their contribution to angiogenesis remains unclear. Here we used synthetic TLR9 agonists, cytosine-phosphate-guanosine oligodeoxynucleotides (CpG-ODN), to investigate the role of TLR9 in vascular pathophysiology and identify potential therapeutic translation. We demonstrate that CpG-ODN stimulates inflammation yet inhibits angiogenesis. Regulation of angiogenesis by CpG-ODN is pervasive and tissue non-specific. Further, we noted that synthetic CpG-ODN requires backbone phosphorothioate but not TLR9 activation to render and maintain endothelial stalk cells quiescent. CpG-ODN pre-treated endothelial cells enhance macrophage migration but restrain pericyte mobilisation. CpG-ODN attenuation of angiogenesis, however, remains TLR9-dependent, as inhibition is lost in TLR9 deficient mice. Additionally, CpG-ODNs induce an M1 macrophage phenotype that restricts angiogenesis. The effects mediated by CpG-ODNs can therefore modulate both endothelial cells and macrophages through distinct pathways, providing potential therapeutic application in ocular vascular disease.
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Project description:Astrocytes' Radiation Response
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