**5. Conclusion**

330 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

expression into the brain (Chen et al. 2009). Promising results have also been obtained with dexamethasone and fluocinolone in several studies, i.e. dexamethasone reduces astroglial reactivity to implanted neuroprosthetic devices in rat cortex (Spataro et al. 2005), whereas intravitreous administration of fluocinolone attenuates retinal degeneration (Glybina et al. 2010). Further evidence suggests that dexamethasone produces immunosuppressive effects on the astrocyte response to interleukin-1-beta stimulation (Pousset et al. 1999) and counteracts blood–brain barrier failure by decreasing transendothelial permeability (Cucullo

Despite synthetic glucocorticoids have demonstrated an adequate safety profile, increasing clinical experience and experimental studies indicate that corticoids are able to promote cognitive dysfunction, anxiety, cerebral atrophy, depression and steroid psychosis. One of the first studies that associated the glucocorticoid delivery with mood disorders in humans was reported in prednisone-treated asthmatic children (Bender et al. 1991). However, adults are also affected by corticoids as demonstrated in healthy volunteers that, after receiving a high-dose prednisone or dexamethasone, showed mood changes and memory impairment (Keenan et al. 1996; Schmidt et al. 1999; Wolkowitz 1994). Cerebral atrophy was reported after a long-term treatment with glucocorticoids in patients with no previous history of central nervous system affection (Bentson et al. 1978; Hara et al. 1981). Other immunologic disorders, such as systemic corticosteroid hypersensitivity (de Sousa et al. 2010; Rachid et al. 2011), toxic epidermal necrolysis (Navarro Llanos et al. 1996) or urticaria-angioedema (Gomez et al. 2002), have also been associated with the administration of glucocorticoids. Under specific circumstances synthetic corticoids may impair or even potentiate the progress of neurological disorders as reported in experimental models of Alzheimer's disease, hypoxia or prenatal glucocorticoid delivery. This fact appears to be particularly important in neurodegenerative disorders related to oxysterol production such as Alzheimer's disease and multiple sclerosis. Oxysterols are oxidized forms of cholesterol that provokes oligodendrocyte apoptosis. Dexamethasone exacerbates the apoptotic effects of oxysterols on oligodendrocytes, resulting in secondary necrosis (Trousson et al. 2009). Cerebral vasculature is also altered by exposure to dexamethasone that may deteriorate hippocampal functions (Neigh et al. 2010). In hypoxia models, dexamethasone increases the expression of Bnip3, a pro-apoptotic Bcl-2 family, which impairs hypoxic tissue damage

Neuronal function and survival are also affected by synthetic corticoids. Dexamethasone increases oxidative stress and expression of monoamine oxidase A and B, resulting in a higher loss of dopaminergic neurons (Arguelles et al. 2010). Oral administration of prednisone or deflazacort promotes neuronal degeneration of pyramidal neurons in CA1 and CA3 hippocampal regions (Gonzalez-Castaneda et al. 2007; Gonzalez-Perez et al. 2007; Ramos-Remus et al. 2002). Dexamethasone also decreases the number of neurons in the striatum (dorsomedial caudate-putamen) and hippocampus (dentate gyrus, CA1 and CA3 subfields), which may account for some of the cognitive deficits seen following administration of glucocorticoids to healthy volunteers (Haynes et al. 2001). Glucocorticoids also target the developing brain as reported in children exposed to synthetic glucocorticoids *in uterus,* who showed a reduction in fetal and, in some cases, newborn and infant HPA axis activity (Tegethoff et al. 2009). Other studies indicate that prenatal dexa- or betamethasone exposure also affects postnatal cognitive functions (Hauser et al. 2007; Hauser et al. 2006), reduces the survival of cholinergic neurons (Emgard et al. 2007), and produces permanent changes in the cytoarchitecture within midbrain dopamine nuclei (McArthur et al. 2005).

et al. 2004).

(Sandau & Handa 2007).

Synthetic glucocorticoids are a valuable therapeutic strategy against neuroinflammation and autoimmune disorders with neurological involvement. In fact, anti-inflammatory strategies receive growing attention for their potential to prevent pathological deterioration in multiple sclerosis (the most prevalent chronic autoimmune disease of the central nervous system), Parkinson's disease, autoimmune encephalomyelitis and other severe neurological disorders. Nevertheless, the uncontrolled use of glucocorticoids must be avoided because of their deleterious potential on cognition, neuronal survival and apoptosis induction. Yet, in those clinical situations where glucocorticoid use is necessary, a continuous neuropsychological assessment is strongly recommended to detect a possible neurological deterioration.
