STEROIDOGENIC ACUTE REGULATORY PROTEIN IN THE BRAIN E. LAVAQUE, a A. SIERRA, b I. AZCOITIA c AND L. M. GARCIA-SEGURA a * a Instituto Cajal, CSIC, Avenida Doctor Arce 37, E-28002 Madrid, Spain b Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10021, USA c Departamento de Biología Celular, Facultad de Biología, Universidad Complutense, E-28040 Madrid, Spain Abstract—The nervous system synthesizes steroids that reg- ulate the development and function of neurons and glia, and have neuroprotective properties. The first step in steroido- genesis involves the delivery of free cholesterol to the inner mitochondrial membrane where it can be converted into pregnenolone by the enzyme cytochrome P450side chain cleavage. The peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein are involved in this process and appear to function in a coordinated manner. Steroidogenic acute regulatory protein mRNA and protein are widely expressed throughout the adult brain. Steroidogenic acute regulatory protein expression has been detected in many neuronal populations, in ependymocytes, in some as- troglial cells, in Schwann cells from peripheral nerves and in proliferating cells of the developing and adult brain. Steroi- dogenic acute regulatory protein is colocalized in the same neural cells with P450side chain cleavage and with other steroidogenic enzymes. Steroidogenic acute regulatory protein expression in the brain shows marked changes with develop- ment, aging and injury. The steroidogenic acute regulatory protein gene may be under the control of diverse mecha- nisms in different neural cell types, since its expression is upregulated by cyclic AMP (cAMP) in gliomas and astrocytes in culture and downregulated by cyclic AMP (cAMP) in Schwann cells. In addition, activation of N-methyl-D-aspartate receptors, and the consequent rise in intracellular calcium levels, activates steroidogenic acute regulatory protein and steroidogenesis in hippocampal neurons. In conclusion, ste- roidogenic acute regulatory protein is regulated in the ner- vous system by different physiological and pathological con- ditions and may play an important role during brain develop- ment, aging and after injury. © 2005 Published by Elsevier Ltd on behalf of IBRO. Key words: neurodegeneration, neurogenesis, oxysterols, peripheral-type benzodiazepine receptor, pregnenolone, steroidogenesis. It is now well accepted that the nervous system is a ste- roidogenic tissue (Baulieu, 1997, 1998; Mellon et al., 2001; Stoffel-Wagner, 2003). Both the central and the peripheral nervous systems express enzymes involved in the synthe- sis and metabolism of steroids. These include the cyto- chrome P450side chain cleavage (P450scc) enzyme, which catalyzes the conversion of cholesterol into preg- nenolone, the precursor for glucocorticoids, mineralocorti- coids and sex steroids. The synthesis of pregnenolone is the first enzymatic step of steroidogenesis. However, there is a previous step that is rate limiting and hormonally regulated: the transfer of cholesterol from the outer to the inner mitochondrial membrane, where P450scc is located. Proteins located in the mitochondrial membranes, such as the peripheral benzodiazepin receptor (PBR) and the ste- roidogenic acute regulatory protein (StAR), allow choles- terol to cross the hydrophilic intermembrane space (Hauet et al., 2005). PBR was initially described on peripheral tissues as a second binding site for diazepam, which binds with higher affinity to GABA A receptors on the nervous system (Braestrup and Squires, 1977). Since then, many studies have demonstrated that PBR is pharmacologically and structurally distinct from the central benzodiazepine/ GABA A receptors. PBR is an 18-kDa peptide located pre- dominantly in the mitochondrial membranes (Anholt et al., 1986; Papadopoulos et al., 1994) and represents a critical component of the permeability transition pore, a multipro- tein complex implicated in the regulation of apoptosis (Ga- liegue et al., 2003; Chelli et al., 2004; Kunduzova et al., 2004; Marselli et al., 2004; Veenman et al., 2004). In addition, PBR has been related with the regulation of sev- eral physiological events, including the control of steroido- genesis (Papadopoulos et al., 1997; Brown and Papado- poulos, 2001; Casellas et al., 2002; Lacapere and Pap- adopoulos, 2003). PBR is expressed in the nervous system, predomi- nantly in glial cells (Vowinckel et al., 1997; Kuhlmann and Guilarte, 2000; Casellas et al., 2002; Wilms et al., 2003). In addition, different forms of neural injury and different neuro- pathological conditions result in the induction of the expression of PBR in the areas of the nervous system involved in the neurodegenerative events. The induction of PBR expression after injury in the CNS is mainly restricted to microglia and astrocytes (Vowinckel et al., 1997; Kuhlmann and Guilarte, 2000; Casellas et al., 2002; Wilms et al., 2003), although a recent study has shown induction of PBR in dorsal root ganglion neurons following injury to the sciatic nerve (Karchewski et al., 2004). The induction of PBR expression after neural injury suggests that this molecule may be involved in the response of the neural tissue to cope with the neurodegenerative process. Indeed, it has been reported that SSR180575, a pyridazi- noindole derivative that possesses a high affinity for the *Corresponding author. Tel: +34-915654729; fax: +34-915854754. E-mail address: lmgs@cajal.csic.es (L. M. Garcia-Segura). Abbreviations: ABCA1, ATP-binding cassette transporter A1; cAMP, cyclic AMP; GFAP, glial fibrillary acidic protein; LXRs, nuclear hor- mone liver X receptors; NMDA, N-methyl-D-aspartate; PBR, peripheral benzodiazepin receptor; P450scc, P450side chain cleavage; StAR, steroidogenic acute regulatory protein. Neuroscience xx (2005) xxx 0306-4522/05$30.00+0.00 © 2005 Published by Elsevier Ltd on behalf of IBRO. doi:10.1016/j.neuroscience.2005.05.060 1 ARTICLE IN PRESS