Function, regulation, and pharmacological effects of pregnenolone in the central nervous system

Lin, Yiqi; Cheung, Garett; Espinoza, Nidia; Papadopoulos, Vassilios

doi:10.1016/j.coemr.2021.100310

Cited by 6 publications

(11 citation statements)

References 64 publications

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“…To our knowledge, there have only been two reports of CYP11A1 protein in the human brain, but the presence was only demonstrated in small areas of the cerebellum and frontal cortex in a few numbers of cells (34,35). The levels of pregnenolone found in the brain and the ability for the brain to produce increased amounts of pregnenolone in response to treatment with TSPO ligands (13,36) creates a discrepancy with the local CYP11A1 levels, suggesting that alternative pathways may be used to produce pregnenolone in the brain (33). To examine this discrepancy, we determined the expression of CYP11A1 in four human glial cell lines.…”

mentioning

confidence: 93%

“…Neurosteroids such as DHEA and pregnenolone sulfate can modulate activity of N-methyl-D-aspartate receptors and have been proposed to play important roles in neuronal plasticity and neuronal cell differentiation (10)(11)(12). Pregnenolone not only serves as the precursor to all other neurosteroids but also has physiological and pharmacological effects on its own (for review, see (13)). For example, administration of pregnenolone can enhance memory in mice (14,15).…”

mentioning

confidence: 99%

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The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells

Lin¹,

Cheung²,

Porter³

et al. 2022

Journal of Biological Chemistry

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confidence: 93%

mentioning

confidence: 99%

The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells

Lin¹,

Cheung²,

Porter³

et al. 2022

Journal of Biological Chemistry

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“…Overall, our findings demonstrate an increase of PREG levels and its downstream derivatives in comatose patients with CM, but causality remains to be established. Remarkably, PREG can modulate myelination, neuroinflammation, neurotransmission, and neuroplasticity in the brain, with potential important beneficial effects on cognition, aging, and addiction 46 . In addition, it promotes the degradation of key proteins in the innate immune signaling to suppress inflammation 42 .…”

Section: Discussionmentioning

confidence: 99%

Upregulation of steroidogenesis is associated with coma in human cerebral malaria

Abdrabou

Gupta

Sahu

et al. 2023

Preprint

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P. falciparum parasites manipulate host metabolic processes during malaria to ensure their survival and progression, causing the host and parasite metabolic pathways to become intertwined. We analyzed metabolites to evaluate their potential as biomarkers for cerebral malaria (CM). Our analysis of CM (with coma) and CM-like (without coma) patients identified 835 metabolites, including lipids, amino acids, xenobiotics, peptides, nucleotides, carbohydrates, cofactors, and vitamins. Principal component analysis revealed clear segregation between CM-like and CM patients. Metabolite-by-metabolite analysis identified 103 differentially abundant metabolites, 26 of which were significantly lower in CM-like patients (primarily lipids), while 71% of those higher in CM patients were amino acids and xenobiotics. The results revealed significant differences in circulating levels of long chain free fatty acids and catecholamine metabolism and identified steroid biosynthesis as the most enriched lipid metabolism pathway, with eight endogenous steroids showing significantly higher levels in CM patients compared to CM-like patients (FC > 2, B-H FDR-adjusted P < 0.05). These steroids include pregnenolone sulfate, pregnenediol sulfate, pregnenetriol sulfate, androsterone monosulfate, 16α-OH-DHEA-S, DHEA-S, cortisol, and cortisone. High levels of pregnenolone and its downstream metabolic derivatives were significantly associated with coma in CM patients. Our findings suggest that monitoring circulating neurosteroid levels in patients could aid in the early identification of those at risk of coma, and may important implications for the clinical management of CM patients.

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“…77 TSPO-specific ligands are also known to increase glucocorticoid and corticosteroid levels 61 and have been shown to affect neurosteroid production. [90][91][92] Accordingly, the use of TSPO ligands as a therapeutic approach to treat neurological and psychiatric disorders have also been investigated. 93 Similarly, the use of TSPO ligands may also induce anxiolytic-like responses, as ligand treatment has been shown to counteract panic attacks in rodents.…”

Section: Tspo Ligandsmentioning

confidence: 99%

“…However, serum LH levels may also become increased following TSPO drug ligand treatment likely because of an effect of the ligand on brain TSPO, 88,89 suggesting that using this target may enhance testosterone biosynthesis by either stimulating the Leydig cell steroidogenic machinery and/or by elevating LH release 77 . TSPO‐specific ligands are also known to increase glucocorticoid and corticosteroid levels 61 and have been shown to affect neurosteroid production 90–92 . Accordingly, the use of TSPO ligands as a therapeutic approach to treat neurological and psychiatric disorders have also been investigated 93 .…”

Section: Endogenous Targets For Testosterone Recovery Therapymentioning

confidence: 99%

Testosterone recovery therapy targeting dysfunctional Leydig cells

Garza

Papadopoulos

2022

Andrology

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Reduced serum testosterone affects millions of men across the world and has been linked to several comorbidities, metabolic dysfunctions, and quality of life changes. The standard treatment for testosterone deficiency remains testosterone replacement therapy. However, limitations on its use and the risk of significant adverse effects make alternative therapeutics desirable. Studies on the mechanisms regulating and synthesizing testosterone formation in testicular Leydig cells demonstrate numerous endogenous targets that could increase testosterone biosynthesis, which could alleviate reduced testosterone effects. Testosterone biosynthesis is facilitated by a conglomerate of cytosolic and mitochondrial proteins that facilitate cholesterol translocation into the mitochondria, the rate‐limiting step in steroidogenesis. An effective therapeutic approach would be required to increase endogenous testosterone formation by enhancing steroidogenesis in Leydig cells. Numerous ligands for steroidogenic proteins have been developed, which increase steroid hormone formation. However, off‐target effects on neurosteroid and adrenal steroid formation may limit their clinical use. First‐in‐class biologics, such as voltage‐dependent anion channel peptides and transplantation of induced human Leydig‐like cells offer advances in the development of specific strategies that could be used to enhance endogenous steroid formation in hormone deficient patients.

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Function, regulation, and pharmacological effects of pregnenolone in the central nervous system

Cited by 6 publications

References 64 publications

The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells

The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells

Upregulation of steroidogenesis is associated with coma in human cerebral malaria

Testosterone recovery therapy targeting dysfunctional Leydig cells

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