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Singh, M.;  Agarwal, V.;  Jindal, D.;  Pancham, P.;  Agarwal, S.;  Mani, S.;  Tiwari, R.K.;  Das, K.;  Alghamdi, B.S.;  Abujamel, T.S.; et al. Biogenesis and Expression of Corticosteroids in the Brain. Encyclopedia. Available online: https://encyclopedia.pub/entry/40912 (accessed on 29 April 2026).
Singh M,  Agarwal V,  Jindal D,  Pancham P,  Agarwal S,  Mani S, et al. Biogenesis and Expression of Corticosteroids in the Brain. Encyclopedia. Available at: https://encyclopedia.pub/entry/40912. Accessed April 29, 2026.
Singh, Manisha, Vinayak Agarwal, Divya Jindal, Pranav Pancham, Shriya Agarwal, Shalini Mani, Raj Kumar Tiwari, Koushik Das, Badrah S. Alghamdi, Tukri S. Abujamel, et al. "Biogenesis and Expression of Corticosteroids in the Brain" Encyclopedia, https://encyclopedia.pub/entry/40912 (accessed April 29, 2026).
Singh, M.,  Agarwal, V.,  Jindal, D.,  Pancham, P.,  Agarwal, S.,  Mani, S.,  Tiwari, R.K.,  Das, K.,  Alghamdi, B.S.,  Abujamel, T.S.,  Ashraf, G.M., & Jha, S.K. (2023, February 07). Biogenesis and Expression of Corticosteroids in the Brain. In Encyclopedia. https://encyclopedia.pub/entry/40912
Singh, Manisha, et al. "Biogenesis and Expression of Corticosteroids in the Brain." Encyclopedia. Web. 07 February, 2023.
Biogenesis and Expression of Corticosteroids in the Brain
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This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13030337

Corticosteroids are the kinds of steroidal hormones that are either produced by the body or are artificially synthesized. The biosynthesis of these hormones occurs from cholesterol within the adrenal cortex site, which is also known as the primary site of several steroidogenic biosynthetic reactions.

genetic variants epigenetic factors Corticosteroids Gene Regulation Glucocorticoids Mineralo Corticosteroids

1. Introduction

Corticosteroids (CCSs) have been used to treat a variety of inflammatory conditions as an immunosuppressive medication for decades. However, many CCSs, including prednisone, methylprednisolone, dexamethasone, and adreno corticotropic, have been shown to have adverse psychiatric consequences [1]. Despite being an efficacious and resolute drug for anti-inflammatory reactions, it is also an immunosuppressive medicine; however, its frequent use globally has also led to an increase in mental health issues and concerns [2]. Corticosteroids inhibit the synthesis of inflammatory proteins while increasing the release of anti-inflammatory ones by various signaling pathways such as nuclear factor kappa B (NF—ƙB), mitogen-activated protein kinase (MAP kinase), etc., but while doing so, they cause other concerns such as immunosuppression, osteoporosis, glaucoma, hypertension, growth retardation, etc., [3].

2. Biogenesis and Expression of Corticosteroids in the Brain

Corticosteroids are the kinds of steroidal hormones that are either produced by the body or are artificially synthesized [4]. The biosynthesis of these hormones occurs from cholesterol within the adrenal cortex site, which is also known as the primary site of several steroidogenic biosynthetic reactions [5]. Mostly, such manifestations are caused by the ultradian or circadian variations and external artificial administration, or are elicited in response to a certain stressful stimulus [6]. The mechanism of action for both GR and MR highly overlaps due to their shared and almost identical DNA-binding domains, yet their expression significantly differs as genes regulated by them are not common [7]. The 21 hydroxylase and 17 α-hydroxylase enzymes are strongly associated with the synthesis of CCS hormones in the human system [8] and P450c17 is the only enzyme mediating the activity of both 17,20-hydroxlyase and 17 α -hydroxylase (steroid 17 alpha-monooxygenase, EC 1.14.99.9) during the synthesis of steroid hormones [9]. Then, there are P450c17 isozymes that are proposed to mediate the same in the testis and adrenal glands. Next, pregnenolone is transformed into mineralocorticoids because the adrenal zona glomerulosa lacks P450c17 activities and the same pregnenolone is transformed into glucocorticoid cortisol in the zona fasciculata because there is a presence of active 17-hydroxylase [10][11]. Both these processes take place in the zona reticularis, where pregnenolone is transformed into sex steroids. Electron transport is the main mechanism controlling the 17, 20-lyase process from NADPH via POR (P450-oxidoreductase) [12].
The CCS expression profile also exhibits altered cellular mechanics in response to stress levels and is extensively influenced by CCS and stress hormone interplay along with the effects facilitated by GR and MR [13]. Such expressional interplaying response systems further add to complexity at the cellular level. Several prior research studies have suggested that only a balanced response, calibrated between the two systems, can potentially lead to resilience. This balance can be hampered by several distinct conditions such as unremitting exposure to stress, especially in genetically vulnerable individuals, which can cause the aggravated manifestation of the pathology, and such cases are not only restricted to psychiatric disorders but instead extend to several neurological pathologies [14].
Another perspective for the involvement of CCSs in initiating the progression of NPDs is the perfusion of MR and GR in the neuronal cells of the hippocampus under the limbic system, confirmed further by various diagnostic studies in autoradiography, in situ hybridization, and radioligand-binding analysis [15], since a hippocampus region in CNS is directly involved with mood and stress response, controlled by the hypothalamic–pituitary–adrenal (HPA) axis [16]. It has also been noted that the limbic system supports interaction between GR and MR, wherein MR exhibits a higher affinity towards corticosterone (CORT) and aldosterone (ALDO) binding [17], though its perfusion at the CORT site is 2–3 fold higher in comparison to the general receptor concentration circulating in the CNS. However, GR expresses 6–10 fold lower affinity than MR, [18][19].

2.1. Gene Regulation by Glucocorticoids (GR)

Corticosteroids are sub-classified as one of the steroidal molecules and thus, GR also belongs to the nuclear hormone receptor superfamily; thus, such receptors exhibit distinct expression over ligand-activated transcription factors [20]. The glucocorticoid is constituted of three chief modular structural domains: N-Terminal Domain (NTD), Ligand Binding Domain (LBD), and DNA Binding Domain (DBD), and these domains further facilitate their expression independently [21]. The NTD is known to be highly influential in the transcriptional machinery as it contains several transactivation regions such as AF1 (Activation Factor 1) / tau1/enh2 [22][23]. Moreover, the AF1 region acquires folded conformation that under specific physiological conditions binds to the GR response element (GRE), resulting in the triggering of gene regulation (Reddy et. Al) [24], and this alteration in the genetic sequence of GRE initiates the conversion of the co-repressor to a co-activator expression. Xavier et al. (2016), in their study, observed that co-repressor protein GRIP 1 (Glutamate receptor-interacting protein 1) molecules increase their co-activator properties when they bind with GR, located on specific GRE [25]. In addition to this, GR co-activator complex models are also responsible for recruiting additional co-activator molecules to the assembly [26].

2.2. Gene Regulation by Mineralo Corticosteroids (MR)

One of the decisive roles in MR response is the moderation and regulation of MR expression levels [13]. It exerts its expression in the hippocampal region for balancing functional action. The hormones in the CNS such as progesterone, as well as serotonin, control the MR mRNA expression [27]. Additionally, it has been observed that after interacting or binding to a ligand molecule, the MR travels to the nucleus and initiates itself to function as a transcription factor. The MR has firm binding specifically to the Human Response Element (HRE), located at 10 kb downstream/upstream from the transcriptional site [28]. Some studies have categorized MR as a ubiquitin transcription factor. Its real-time PCR quantification presents various interesting anatomical expressions that show MR regulation elevating its expression in CNS rather than GR [29]. In humans, aldosterone is identified as the most important natural ligand to the MR, besides cortisol that aids in facilitating MR’s expression at the messenger or at the protein level in cells where either of these two ligands have been found to regulate the process [30]. Furthermore, it has been reported that epithelial expressions of MR have always been associated with a simultaneous expression of 11 β-hydroxy steroid dehydrogenase 2 (11β-HSD2), permitting the aldosterone to selectively activate the MR, by primarily converting the GR hormones to their 11-keto analogs [31][32].

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  8. Baumgartner-Parzer, S.; Witsch-Baumgartner, M.; Hoeppner, W. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. Eur. J. Hum. Genet. 2020, 28, 1341–1367.
  9. Chung, B.C.; Picado-Leonard, J.; Haniu, M.; Bienkowski, M.; Hall, P.F.; Shively, J.E.; Miller, W.L. Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): Cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc. Natl. Acad. Sci. USA 1987, 84, 407–411.
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  11. Lorence, M.C.; Murry, B.A.; Trant, J.M.; Mason, J.I. Human 3 beta-hydroxysteroid dehydrogenase/delta 5→4isomerase from placenta: Expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology 1990, 126, 2493–2498.
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Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Manisha Singh , Vinayak Agarwal , Divya Jindal ,
Pranav Pancham
, Shriya Agarwal , Shalini Mani , Raj Kumar Tiwari ,
Koushik Das
, Badrah S. Alghamdi , Tukri S. Abujamel , Ghulam Md. Ashraf , Saurabh Kumar Jha
View Times: 779
Revisions: 2 times (View History)
Update Date: 14 Feb 2023
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