Medical Youth Mini review articles Volume 67 | No. 1 | March 2016. 35 Te role of neurosteroids in the pathogenesis of hepatic encephalopathy Sažetak Hepatična encefalopatija (HE) predstavlja neuropsihi- jatrijski sindrom uzrokovan akutnom ili hroničnom insufci- jencijom jetre. Glavnu ulogu u patogenezi HE ima hiperamo- nijemija. Mehanizmi kojima amonijak izaziva razvoj HE su poremećaji neurotransmisije, oksidativni stres, neuroinfama- cija, mitohondrijska disfunkcija i energetski defcit. Neuroste- roidi značajno doprinose povećanoj GABA-ergičkoj aktivnosti u HE. Amonijak u kombinaciji sa manganom i proinfama- tornim citokinima stimuliše sintezu neurosteroida ushodnom regulacijom translokatorskog proteina, komponentom multi- proteinskog kompleksa koja stimuliše transport holesterola u mitohondrije astrocita. Holesterol služi kao supstrat za sintezu neurosteroida alopregnanolona i tetrahidrodeoksikortikoste- rona. Nakon oslobađanja iz astrocita alopregnanolon i tetrahi- drodeoksikortikosteron pojačavaju GABA-ergičku transmisiju pozitivnom alosternom modulacijom GABAA receptora, čime doprinose poremećajima ciklusa budnost-spavanje i kognitiv- nim poremećajima u HE. Dodatni potencijalni mehanizmi dej- stva neurosteroida u HE uključuju modulaciju aktivnosti sero- toninergičkih, holinergičkih, glicinergičkih, glutamatergičkih i opioidnih receptora, kao i modulaciju genske ekspresije. Cilj ovog preglednog rada je bio da prikaže dosadašnja saznanja o ulozi neurosteroida u patogenezi HE. Ključne reči: neurosteroidi, hepatična encefalopatija, amonijak, neurotransmisija Abstract Hepatic Encephalopathy (HE) represents a neuropsy- chiatric syndrome caused by acute or chronic liver failure. Hy- perammonemia plays a pivotal role in the development of HE through modulation of neurotransmission, oxidative stress, neuroinfammation, mitochondrial dysfunction, and ener- gy defcit. Neurosteroids contribute signifcantly to increased GABAergic tone in HE. Ammonia, in combination with manganese and proinfammatory cytokines, stimulate neuro- steroid synthesis by up-regulation of translocator protein, a component of multiprotein complex that stimulate cholesterol transport into astrocytic mitochondria. Cholesterol serves as a substrate for the synthesis of neurosteroids allopregnano- lone and tetrahydro-deoxycorticosterone. Afer release from astrocytes, allopregnanolone and tetrahydro-deoxycorticoste- rone potentiate GABAergic transmission by positive allosteric modulation of GABAA receptor, thus contributing to cognitive defcit and alterations in sleep-wake cycle. Additional potential mechanisms of neurosteroid action in HE include modulation of serotoninergic, cholinergic, glutamatergic, glycinergic, and opioid receptor activities, as well as modulation of gene expres- sion. Tis review aimed to summarize current knowledge of the role of neurosteroids in the pathogenesis of HE. Key words: neurosteroids, hepatic encephalopathy, ammonia, neurotransmission Uloga neurosteroida u patogenezi heapatične encefalopatije Dušan Mladenović 1 , Olivera Stanojlović 2 , Tatjana Radosavljević 1 1 Institut za patološku fziologiju, Medicinski fakultet, Univerzitet u Beogradu 2 Institut za medicinsku fziologiju ,,Rihard Burijan‘‘, Univerzitet u Beogradu Kontakt: dmladen@med.bg.ac.rs Introduction Hepatic Encephalopathy (HE) represents a com- plex neuropsychiatric syndrome caused by acute or chronic liver failure (1). It may be presented in three ma- jor forms: type A (caused by acute liver failure), type B (caused by porto-systemic shunt without liver disease), and type C HE (associated with liver cirrhosis) (2). Type A HE has a rapid course with deterioration of mental functions, convulsions and the loss of conciousness. On the other hand, signs and symptoms of chronic HE (usu- ally type C) may vary from subtle cognitive dysfunction and attention defcits, which cannot be detected by the standard neurological exam (minimal HE), to the devel- opment of hepatic coma in the stage 4 of HE (2,3). Te pathogenesis of HE is complex and not fully established. In type A HE hyperammonemia, along with other toxins, induces cytotoxic brain edema due to the swelling of astrocytes, with subsequent rise in intracranial pressure (4). Tis may potentially lead to the fatal outcome due to the brainstem herniation in the foramen magnum.