**2. Glucocorticoids**

The hypothalamus-pituitary-adrenal axis exerts an important regulation on neural functions mediated by the releasing of steroid molecules named corticosteroids. These hormones are synthesized from cholesterol in the cortex of adrenal glands (Fietta et al., 2009; Nicolaides et al., 2010). Two types of corticoids have been identified: glucocorticoids and mineralocorticoids. Glucocorticoids are produced in the inner region of the adrenal cortex (fascicular zone), while mineralocorticoids are synthesized in the outer part of the adrenal

Synthetic Glucocorticoids Modulate Function of Neural

(Tegethoff et al. 2009).

immunosuppressive activity.

Cells: Implications in Autoimmune Neurological Disorders 325

differs from cortisol only by a δ-1-dihydro configuration. Instead, bexamethasone and betamethasone have additional 9-α-fluoro and 16-β- or 16-α-methyl groups, respectively

Fig. 2. Chemical structures of glucocorticoids. A. Metabolic pathways in the adrenocortical

Endogenous and synthetic glucocorticoids regulate a number of physiological and behavioural responses via intracellular receptors, which modulate the function of neural cells. In several brain regions, neural cells express two types of corticoid receptors: Type-1 receptors, also called mineralocorticoid receptors (MRs), and Type-2 receptors, also called glucocorticoid receptors (GRs) or NR3C1 (nuclear receptor subfamily 3, group C, member 1) (Fietta et al. 2009; Hoppmann et al. 2010; Marques et al. 2009; Prager et al. 2010). NR3C1

hormone biosynthesis. B. Synthetic glucocorticoids with anti-inflammatory and

cortex (glomerular zone) (Schimmer & George 1998). The name mineralocorticoid derives from early observations that associated these hormones with the homeostasis of sodium and water, whereas glucocorticoids obtained their name from initial observations that these steroids were involved in the metabolism of glucose. To date, it is well accepted that glucoand mineralocorticoids have a number of pleiotropic and systemic effects (Figure 1) on cardiovascular system (Schimmer & George 1998; Ullian 1999), erythropoiesis (Amylon et al. 1986; King et al. 1988), calcium and bone metabolism (Thacker 2010), gastrointestinal tract (Black 1988), nitrogen excretion and glucose metabolism (Schimmer & George 1998), and exert a strong regulation in the immune system (Silverman et al. 2005). These physiological properties of glucocorticoids are useful in clinical medicine to treat and control a broad spectrum of diseases, such as: allergies, autoimmune diseases, cancer, hormonal replacement, asthma and sepsis. Nevertheless, glucocorticoids also have potentially harmful effects on several body systems, including the central nervous system. Some of these neurological impairments will be discussed below.

Fig. 1. Physiological effects of glucocorticoids and the hypothalamus-pituitary-adrenal axis. CRF = corticotropin-releasing factor ; ACTH = adrenocorticotrophin hormone; (+) indicates stimulation and (-) indicates inhibition.

#### **3. Synthetic glucocorticoids**

Synthetic glucocorticoids are usually synthesized from cholic acid obtained from cattle or steroid sapogenins found in plants. The chemical structure of these drugs is slightly different from that of natural glucocorticoids (Figure 2 A - B). For example, prednisolone

cortex (glomerular zone) (Schimmer & George 1998). The name mineralocorticoid derives from early observations that associated these hormones with the homeostasis of sodium and water, whereas glucocorticoids obtained their name from initial observations that these steroids were involved in the metabolism of glucose. To date, it is well accepted that glucoand mineralocorticoids have a number of pleiotropic and systemic effects (Figure 1) on cardiovascular system (Schimmer & George 1998; Ullian 1999), erythropoiesis (Amylon et al. 1986; King et al. 1988), calcium and bone metabolism (Thacker 2010), gastrointestinal tract (Black 1988), nitrogen excretion and glucose metabolism (Schimmer & George 1998), and exert a strong regulation in the immune system (Silverman et al. 2005). These physiological properties of glucocorticoids are useful in clinical medicine to treat and control a broad spectrum of diseases, such as: allergies, autoimmune diseases, cancer, hormonal replacement, asthma and sepsis. Nevertheless, glucocorticoids also have potentially harmful effects on several body systems, including the central nervous system. Some of

Fig. 1. Physiological effects of glucocorticoids and the hypothalamus-pituitary-adrenal axis. CRF = corticotropin-releasing factor ; ACTH = adrenocorticotrophin hormone; (+) indicates

Synthetic glucocorticoids are usually synthesized from cholic acid obtained from cattle or steroid sapogenins found in plants. The chemical structure of these drugs is slightly different from that of natural glucocorticoids (Figure 2 A - B). For example, prednisolone

these neurological impairments will be discussed below.

stimulation and (-) indicates inhibition.

**3. Synthetic glucocorticoids** 

differs from cortisol only by a δ-1-dihydro configuration. Instead, bexamethasone and betamethasone have additional 9-α-fluoro and 16-β- or 16-α-methyl groups, respectively (Tegethoff et al. 2009).

Fig. 2. Chemical structures of glucocorticoids. A. Metabolic pathways in the adrenocortical hormone biosynthesis. B. Synthetic glucocorticoids with anti-inflammatory and immunosuppressive activity.

Endogenous and synthetic glucocorticoids regulate a number of physiological and behavioural responses via intracellular receptors, which modulate the function of neural cells. In several brain regions, neural cells express two types of corticoid receptors: Type-1 receptors, also called mineralocorticoid receptors (MRs), and Type-2 receptors, also called glucocorticoid receptors (GRs) or NR3C1 (nuclear receptor subfamily 3, group C, member 1) (Fietta et al. 2009; Hoppmann et al. 2010; Marques et al. 2009; Prager et al. 2010). NR3C1

Synthetic Glucocorticoids Modulate Function of Neural

Cells: Implications in Autoimmune Neurological Disorders 327

Fig. 3. Astrocytes modulate and/or promote several effects into the brain under the influence of glucocorticoids. Corticoids (GCs); glucocorticoid receptor (GR);

mineralocorticoid receptor (MR).

mediates the negative feedback in the HPA axis and in other limbic structures (de Kloet 2003; De Kloet et al. 1998). GRs have tenfold lesser affinity for corticosteroids than MRs (Table 1). The physiological outcome of these interactions is that GRs are mainly active during periods of abundant glucocorticoid secretion, such as circadian peak, systemic inflammation or stress. Thus, some of the functions of GRs include the regulation of energy metabolism, cellular homeostasis, stress-induced response, information storage and retrieval (de Kloet 2003; de Kloet et al. 1999; De Kloet et al. 1998). In contrast, MRs have a high affinity for corticosteroids; as a result, they are active when circulating glucocorticoid levels are relatively low. These receptors are highly expressed in hippocampus, septum, amygdala, frontal cortex, hypothalamic paraventricular nucleus and locus coeruleus (de Kloet 2003; De Kloet et al. 1998). One of the main functions of MRs is the regulation of basal HPA tone (de Kloet 2003; De Kloet et al. 1998).


Table 1. Glucocorticoid affinity in type-1 (11β-HSD1) and type-2 receptors (11β-HSD2). Modified from Buckingham 2006.


Table 2. Potency and plasma half-life of natural and synthetic glucocorticoids commonly used in medicine.

The pharmacological effects of natural and synthetic glucocorticoids are mediated by the same genomic and non-genomic pathways (Buckingham 2006; Lowenberg et al. 2005; Lowenberg et al. 2006). The levels of efficacy, potency and pharmacological activity of synthetic hormones are determined by their pharmacokinetic properties (Table 2) (Fietta et al. 2009; Gonzalez-Perez et al. 2007). In clinic, synthetic glucocorticoids are commonly used as anti-inflammatory drugs for the treatment of allergies, rheumatic diseases, asthma, lymphoproliferative diseases and autoimmune disorders (Liberman et al. 2010). Most, if not all, of them can bind to both MRs and GRs, but with different affinities (Gonzalez-Perez et al. 2007). Remarkably, an increasing number of pre-clinical and clinical studies indicate that synthetic glucocorticoids can modify the citoarchitecture and function of glial cells, which alter the brain homeostasis.

mediates the negative feedback in the HPA axis and in other limbic structures (de Kloet 2003; De Kloet et al. 1998). GRs have tenfold lesser affinity for corticosteroids than MRs (Table 1). The physiological outcome of these interactions is that GRs are mainly active during periods of abundant glucocorticoid secretion, such as circadian peak, systemic inflammation or stress. Thus, some of the functions of GRs include the regulation of energy metabolism, cellular homeostasis, stress-induced response, information storage and retrieval (de Kloet 2003; de Kloet et al. 1999; De Kloet et al. 1998). In contrast, MRs have a high affinity for corticosteroids; as a result, they are active when circulating glucocorticoid levels are relatively low. These receptors are highly expressed in hippocampus, septum, amygdala, frontal cortex, hypothalamic paraventricular nucleus and locus coeruleus (de Kloet 2003; De Kloet et al. 1998). One of the main functions of MRs is the regulation of basal HPA tone (de

> High affinity Cortisol:12 nM Corticosterone: 45 nM Dexamethasone: 140 nM

> > 0.8 1 0.8

25 30-40

Carbenoxolone

Kloet 2003; De Kloet et al. 1998).

**Activity (Km)** Low affinity

Modified from Buckingham 2006.

Cortisol Cortisone Hydrocortisone

Deflazacort Prednisone Prednisolone Methylprednisolone Triamcinolone

Dexamethasone Betamethasone

used in medicine.

**Characteristics 11β-HSD1 11β-HSD2 Molecular mass** 34 kDa 40 kDa

> Cortisol: 17 mM Corticosterone: 20 mM Cortisone: 200 mM

**Inhibitors** Glycerhetinic acid

Table 1. Glucocorticoid affinity in type-1 (11β-HSD1) and type-2 receptors (11β-HSD2).

**Glucocorticoid Plasma half-life Potency** 

**Intermediate t1/2 12-36 h** 

Table 2. Potency and plasma half-life of natural and synthetic glucocorticoids commonly

The pharmacological effects of natural and synthetic glucocorticoids are mediated by the same genomic and non-genomic pathways (Buckingham 2006; Lowenberg et al. 2005; Lowenberg et al. 2006). The levels of efficacy, potency and pharmacological activity of synthetic hormones are determined by their pharmacokinetic properties (Table 2) (Fietta et al. 2009; Gonzalez-Perez et al. 2007). In clinic, synthetic glucocorticoids are commonly used as anti-inflammatory drugs for the treatment of allergies, rheumatic diseases, asthma, lymphoproliferative diseases and autoimmune disorders (Liberman et al. 2010). Most, if not all, of them can bind to both MRs and GRs, but with different affinities (Gonzalez-Perez et al. 2007). Remarkably, an increasing number of pre-clinical and clinical studies indicate that synthetic glucocorticoids can modify the citoarchitecture and function of glial cells, which alter the brain homeostasis.

**Short t1/2 8-12 h** 

**Long t1/2 36–72 h** 

Fig. 3. Astrocytes modulate and/or promote several effects into the brain under the influence of glucocorticoids. Corticoids (GCs); glucocorticoid receptor (GR); mineralocorticoid receptor (MR).

Synthetic Glucocorticoids Modulate Function of Neural

dependent phenomena (Gonzalez-Perez et al. 2001).

**observed in patients upon GCs administration** 

neuronal degeneration.

Cells: Implications in Autoimmune Neurological Disorders 329

proliferation and growth retardation may also be enhanced by a concomitant reduction in the production of insulin-like growth factor 1 (IGF-1) in parenchymal astrocytes (Adamo et al. 1988). On the other hand, the overexpression of GFAP and chondroitin sulfate proteoglycans in reactive astrocytes has been related to a deficient neuronal repair and less neurite outgrowth. Methylprednisolone can revert these adverse effects by downregulating astrocyte activation (Liu et al. 2008) and reducing the number of GFAP-expressing astroglia (Sabolek et al. 2006). Further studies indicate that dexamethasone can modify hippocampal neuron development and survival by decreasing the mRNA levels of nerve growth factor (NGF) (Niu et al. 1997) and GFAP in hippocampus and neocortex (Aleong et al. 2003). In contrast, other reports using corticosterone (Bridges et al. 2008), prednisone (Ramos-Remus et al. 2002) and deflazacort (Gonzalez-Castaneda et al. 2007) reported an increase in the number and cytoplasmic processes of hippocampal and cortical astrocytes. The reason for these discrepancies is not well-known, but they appear to be mediated by dose- and region-

Glucocorticoids not only modify the function of glial cells in adult stages, but also during prenatal development. Prenatal betamethasone administration delays both astrocyte and capillary tight junction maturation (Huang et al. 2001a), as well as the myelination in the corpus callosum (Huang et al. 2001b). Remarkably, glucocorticoid effects are not limited to the modulation of cell morphology or molecular expression in neuroglia. Instead, they are key modulators of glycogen metabolism and neurotransmitter transporter homeostasis as demonstrated in several experimental models. For instance, cortical astrocytes exposed to dexamethasone show a reduction of noradrenaline-induced glycogen synthesis (Allaman et al. 2004). Prednisolone, betamethasone and dexamethasone inhibit the transporter uptake of monoamines producing effects on physiological and behavioral processes (Hill et al. 2010). The glial glutamate transporter-1 (GLT-1) is also affected by synthetic glucocorticoids. In cortical astrocytes, dexamethasone provokes a marked increase in the GLT-1 transcription and GLT-1 protein levels (Zschocke et al. 2005). GABAergic neurons are also affected by synthetic glucocorticoids that impair their rhythmic firing, which may lead to cognitive deficit (Hu et al. 2010). Taken together, this evidence indicates that synthetic glucocorticoids exert a strong modulation on neural cells by modifying protein expression, neurite growth, cell proliferation, neurotransmitter uptake, neuronal firing, vasculature function and

**4.1 Implications in autoimmune neurological disorders. Pathological features** 

One major application of synthetic glucocorticoids is the treatment of acute and chronic neuroinflammatory disorders, such as multiple sclerosis, autoimmune encephalomyelitis, immune rejection, Parkinson's disease, retinal degeneration and others. Increasing evidence indicates that the therapeutic efficacy of glucocorticoids against autoimmune disorders may rely not only on their well-known anti-inflammatory effects, but also on their properties of neuro-gliomodulation (Gonzalez-Perez et al. 2007). For instance, methylprednisolone has a synergistic effect with Nogo-66 receptor protein, which promotes functional recovery and axonal growth in a model of spinal cord contusion (Ji et al. 2005). Methylprednisolone also mediates anti-apoptotic effects on oligodendrocytes by activating STAT5 proteins, which up-regulate a splicing isoform of the bcl-x gene (Xu et al. 2009). On the other hand, prednisone contributes to attenuate experimental autoimmune encephalomyelitis by preventing the reduction of brain-derived neurotrophic factor (BDNF) and NGF mRNA
