in the century of spectacular medical therapies , there is still a lack of substance that may protect the brain cells against neurodegeneration . since the discovery of neurosteroids , scientists have made a great effort to evaluate their function , including possible neuroprotective properties . according to most commonly used definition neurosteroids
cover both steroid hormones , which are synthesized de novo in neurons and glial cells , and their metabolites acting within the central nervous system ( cns ) ( compagnone and mellon , 2000 ) ( figure 1 ) .
hormones may regulate brain function in an autocrine and paracrine manner via membrane or nuclear receptors ( baulieu , 1998 ; baulieu et al .
, 2001 ; plassart - schiess and baulieu , 2001 ; singh , 2006 ) . regular neurosteroids act as positive or negative modulators of neurotransmitter receptors : gamma - amino butyric acid a ( gabaa ) receptor , n - methyl - d - aspartate ( nmda ) receptor , -amino-3-hydroxy-5-methylisoxazole propionate ( ampa ) receptor , sigma-1 ( 1 ) , nicotinic , muscarinic , kainic , serotoninergic and glycine receptors , regulate gene expression , or signaling cascades ( wojtal et al . , 2006 ; borowicz et al . ,
we review the main neurosteroids , including pregnenolone ( preg ) and pregnenolone sulfate ( pregs ) , progesterone ( prog ) , allopregnanolone ( allo ) , dehydroepiandrosterone ( dhea ) , dhea sulfate ( dheas ) , deoxycorticosterone ( doc ) , and tetrahydrodeoxycorticosterone ( thdoc ) .
, preg is a hormone precursor , prog , doc , and dhea represent hormones , while allo ( a prog metabolite ) and thdoc ( a doc derivative ) belong to neurosteroids , which are entirely devoid of hormonal action .
synthetic neurosteroids have even longer half - time , and may be administered orally , in contrast to natural steroids ( wojtal et al . , 2006 ; borowicz et al . ,
neuroprotection involves mechanisms protecting against neuronal injury or degeneration in the central and peripheral nervous system .
all these processes may be a consequence of acute disorders ( e.g. , stroke or nervous system injury ) or chronic neurodegenerative processes ( e.g. , in the course of alzheimer s , parkinson s , and huntington s disease ) . the overriding aim is , of course , to prevent the development of a disease , but it is equally important to limit neuronal dysfunction after the cns injury and maintain undisturbed neural function of the brain with the highest possible cellular integrity . at present , a wide range of neuroprotective products is available or under investigation .
many of them can potentially be used in more than one disorder , because most of the underlying mechanisms of neurodegeneration ( in both acute and chronic disorders ) seems to be quite similar . until recently two mechanisms of cell death were known :
the programmed cell death ( apoptosis ) and unregulated process of necrosis . necrosis and apoptosis differ with numerous morphological and biochemical features . in necrosis ,
extreme physiological conditions ( e.g. , hypoxia ) lead to damage to the plasma membrane .
the whole cell and intracellular organelles , particularly mitochondria , swell , and rapture . as a consequence of loss of membrane integrity ,
this process ends with cell lysis and is often associated with a vast tissue damage resulting from an intense inflammatory response ( majno and joris , 1995 ; kanduc et al .
, 2002 ; van cruchten and van den broeck , 2002 ) . nevertheless , it has been proved that non - apoptotic forms of programmed cell death may also exist .
in fact , three main types of the programmed death has been distinguished : 1 .
autophagic cell death can be activated by ras genes , while type 3 ( cytoplasmic ) was shown to be triggered by stimulation of the insulin - like growth factor i receptor ( igfir ) or the binding of substance p to its neurokinin-1 .
this form , characterized by cytoplasmic vacuolization , lack of apoptotic morphology , and lack of caspase activation , was named paraptosis ( sperandio et al . , 2000 , 2004 , 2010 ; leist and jttel , 2001 ; yakovlev and faden , 2004 ; kroemer et al . , 2009 ) . however , accumulating evidences indicate that necrotic cell death can also be a regulated process . in 2005
the term necroptosis was introduced to describe a little known yet alternative form of cell death  the programmed necrosis ( teng et al . , 2005 ; vandenabeele et al . , 2010 )
necroptosis is defined as a programmed but caspase - independent cell death that activates autophagy and morphologically resembles necrosis ( degterev et al .
whether this form of cell death should be equated with the programmed autophagic form remains uncertain .
this process , in fact intermediate between necrosis and apoptosis , develops often as an answer to hypoxia , reperfusion , and excitotoxicity .
these findings open a possibility to develop new therapeutic strategies that may extend the window for neuroprotection in such disorders as stroke , trauma and neurodegenerative diseases .
interestingly , necrostatin-1 and 5 , lately identified specific and potent small - molecule inhibitors of necroptosis , were shown to block a critical step of the cell death process ( yuan et al . , 2003
; degterev et al . , 2005 ; mehta et al . , 2007 ; wang et al . ,
in fact , research on neuronal death mechanisms may help to develop an effective neuroprotective treatment and contribute to a significant improvement in patient quality of life ( charalampopoulos et al .
pregnenolone , usually considered as a neurosteroid precursor , exhibited neuroprotective effects against glutamate- and amyloid  protein - induced neurotoxicity in clonal mouse hippocampal cell line ( ht-22 ; gursoy et al . , 2001 ) .
enhanced its polymerization and activated neurite outgrowth in nerve growth factor - pretreated clonal rat pheochromocytoma cell line of neuronal crest origin , pc12 ( fontaine - lenoir et al . , 2006 ) , improves myelination ( koenig et al . , 1995 ) .
( 2008 ) preg reduced the staurosporine- and glutamate - induced ldh release and diminished the number of apoptotic cells in primary neuronal cortical cultures . additionally , preg exerted neuroprotective effects against kainate - induced cell death in the hippocampus of gonadectomized rats .
the exact mechanism of preg action is not clear , however , it may be mediated by estradiol , the main product of aromatase action .
fadrozole , an aromatase inhibitor , prevented the neuroprotective effects of both neurosteroids ( veiga et al . , 2003 ) .
in patients with alzheimer s disease , preg concentrations were reduced in the striatum and cerebellum .
interestingly , the negative correlation was shown between preg and the level of cortical -amyloid ( weill - engerer et al .
, 2002 ; luchetti et al . , 2011 ) . in rat hippocampal slices , preg inhibited , or enhanced nmda response .
the former effect appeared in the presence of haloperidol and indicates an indirect  receptor modulation .
the latter one seems to be dependent on a direct nmda receptor response ( monnet et al . , 1995 )
preg , pregnenolone ; prog , progesterone ; allo , allopregnanolone ; dhea , dehydroepiandrosterone ; dheas , dehydroepiandrosterone sulfate ester ; doc , deoxycorticosterone ; thdoc , allotetrahydrodeoxycorticosterone .
progesterone is produced primarily in females in the ovarian corpus luteum and placenta , while in males it is mostly found in testes and adrenal glands . however , this hormone may also be synthesized de novo within the nervous system . initially , it was observed that brain concentrations of prog maintained even in gonadectomized rats ( corpchot et al . , 1983 ) .
then , glial cell cultures were reported to synthesize prog and express prog receptors ( jung - testas et al . , 1989 , 1999 ) .
the hormone and its derivatives are positive modulators of gabaa receptors ( borowicz et al . , 2008 ) .
prog is synthesized in human brain at the similar level in both sexes ( stein and wright , 2010 ) .
identification of neuroprotective properties of this steroid began with the observation of a better recovery of female pseudopregnant rats after the traumatic brain injury ( tbi ; roof et al . , 1993 ) .
the authors observed the inverse correlation between serum prog concentration and degree of brain edema after injury ( wright et al . , 2001 ) . in male and normal cycling female rats , administration of prog ( in the 1st , 6th , 24th , and 48th  h after tbi ) significantly protected animals against the development of brain edema and cognitive impairment ( roof et al .
it could be concluded that the positive effect of prog treatment could be achieved when the steroid is administered within 24  h after injury , although the sooner onset of the treatment means the better outcome .
the optimal dose of prog ranged from 8 to 16  mg / kg ( roof et al .
( 2002 ) tested 3- and 5-days regimen of prog administration after tbi and observed a significant reduction size of injury - induced necrosis and diminished cell loss in the dorsomedial nucleus of the thalamus .
prog , used at low physiological doses in ovariectomized female rats after tbi , reduced alterations in mitochondrial respiration and hippocampal cell loss ( robertson et al . , 2006 ) .
in another study , treatment with prog following tbi diminished production of inflammatory proteins in rats ( pettus et al . , 2005 ) .
this hormone administered after a tbi episode significantly lowered the brain concentration of isoprostaglandin , an established marker of lipid peroxidation .
advantageous properties of prog were also observed in models of the spinal cord and peripheral nerve injury . the hormone administered for 3  days following the spinal cord injury improved myelination , increased the level of brain derived neurotrophic factor ( bdnf ) mrna and reduced chromatolysis ( de nicola et al . , 2006 ) , whereas 5-day administration diminished the size of lesions and prevented secondary neuronal loss ( thomas et al . , 1999 ) . according to labombarda et al .
( 2010 ) prog significantly enhanced bdnf neuronal expression , up - regulated growth - associated protein 43 ( gap-43 ) necessary for axonal regeneration , prevented the injury - induced chromatolytic changes of spinal neurons and increased activity of enzymes crucial for normal neuronal metabolism and neurotransmission , and restored impaired expression of the na , k - atpase subunits and choline acetyltransferase . on the other hand , coughlan et al .
administration of prog following acute spinal cord injury in rats attenuated the loss of microtubule - associated protein 2 , a major component of the cytoskeleton ( gonzlez et al . , 2009 ) .
in addition , this steroid acts as a promyelinating factor by stimulating synthesis of myelin proteins and proliferation / differentiation of oligodendrocyte progenitors ( gonzalez et al . , 2005 ; labombarda et al . ,
yu ( 1989 ) observed that prog treatment following motor neuron axotomy attenuated loss of neurons in rats . according to koenig et al .
the same hormone increased expression of genes coding crucial myelin proteins in rat schwann cells ( dsarnaud et al . , 1998 ) .
in rat peripheral nerves prog increased glial cell growth and differentiation , induced synthesis of myelin - specific proteins in oligodendrocytes , and potentiated the formation of new myelin sheaths by schwann cells ( jung - testas et al .
progesterone administration following the cortical contusion injury protected against secondary neuronal loss and facilitated cognitive recovery in rats ( roof et al .
, 1994 ; asbury et al . , 1998 ) . in the diffused tbi model , administration of physiological doses of prog
reduced cell loss , axonal injury , decreased caspase-3 immunoreactivity , and facilitated the motor and cognitive performance recovery in male and ovariectomized female rats ( oconnor et al . , 2007 ) .
in the model of ischemic injury , treatment with prog reduced brain cell damage , improved neurological outcome in rats ( jiang et al . , 1996 ; chen et al . , 1999
; kumon et al . , 2000 ) , and increased survival rate in mice ( gibson and murphy , 2004 ) . in the study of jiang et al . (
1996 ) the effects were comparable either when the hormone was given immediately before or 2  h after reperfusion .
post - injury administration of prog in rats with the brain global ischemia resulted in a significant reduction of cortical shrinkage and cell loss in the ca1 and ca2 hippocampal subfields .
additionally , the hormone prevented ventricular dilatation compared with control animals ( moral et al .
, 2005 ) . in another study , application of prog and allo after severe transient forebrain ischemia in rats resulted in better functional outcome and preserved dimensions of hippocampal formation despite pyramidal neurons loss ( moral et al . , 2011 )
similarly , in cats after acute global ischemia prog reduced cell loss , especially in the ca1/ca2 areas , and caudate nucleus regions ( gonzlez - vidal et al . , 1998 ; cervantes et al . , 2002 )
this steroid diminished cortical and optionally subcortical infarct volumes ( alkayed et al . , 2000 ) .
both prog and allo improved behavioral outcome of animals ( sayeed et al . , 2007 ) .
recently , cai et al . ( 2008 ) found that acute neuroprotective effects of prog in ischemic brain injury may depend on its antagonistic action toward the 1 receptor and subsequent inhibition of the nmda - induced ca influx .
it was observed that patients with acute tbi , treated with prog , had a lower 30-day mortality rate than control individuals ( wright et al . , 2006 ) .
similarly , lower mortality and better functional outcomes were found in the prog group of patients by xiao et al .
at least two third - phase clinical trials are currently run to confirm neuroprotective properties of this hormone in patients after brain injury ( stein and wright , 2010 ) .
wobbler mice receiving the hormon presented less pronounced neuropathology , reduced number of vacuolated cells , preserved mitochondrial ultrastructure ( gonzalez deniselle et al . , 2002 ) , attenuated motoneuron degeneration and boosted myelination in schwann cells and oligodendrocytes in the cns ( schumacher et al . , 2004 ) .
( 2003 ) prog and its derivatives : dihydroprogesterone ( dhp ) and tetrahydroprogesterone ( thp ) may control the expression of the glycoprotein po peripheral myelin and protein 22 ( pmp22 ) via activation of the prog receptor or gabaa receptor , respectively .
chronic ( 1  month lasting ) treatment with these neurosteroids preserved the nerve conduction velocity , thermal threshold , intra - epidermal nerve fiber density , na(+)k(+)-atpase activity , and mrna levels of myelin proteins ( leonelli et al . , 2007 ) .
neuroprotective action of prog seem to be partially due to reduction of cerebral edema that may be achieved via different mechanisms : protecting or rebuilding the blood  brain barrier ( duvdevani et al . , 1995 ; roof et al . , 1997 ) , modulating aquaporins ( amiry - moghaddam et al . , 2003 ) , up - regulation of membrane prog binding protein 25-dx , which is co - expressed with vasopressin and regulates brain water homeostasis , and reduction of the cytotoxic phase of edema ( guennoun et al . , 2008 ; stein et al . , 2008 ) .
other possible actions of prog include : down - regulation of the inflammatory cascade by decelerating cytokine ( il-1 ; il-6 ; tnf)-induced reactions , slowing the immune cell activation , and migration ( arvin et al .
this neurosteroid limits cellular necrosis and apoptosis by : 1 . lowering the concentration of nuclear factor  and expression of its target genes such as il-1 , c3 , inos , cox2 ( pettus et al . ,
reducing excitotoxicity by inhibition of glutamate receptors , 3 . boosting the effects of gabaa , 4 depression of spontaneous firing of neurons , a possible causative factor of posttraumatic seizures ( bergeron et al .
2005 ; stein , 2008 ) , 5 . stimulation of schwann s cells via nuclear receptor to produce myelin , and reducing glial scarring in the cns ( koenig et al .
, 1995 ; plassart - schiess and baulieu , 2001 ) , 6 . decreasing injury - induced lipid peroxidation and oxidative stress via inhibition of tnf- production or up - regulation of antioxidant enzymes ( roof et al . , 1997 ; stein , 2008 ; stein and wright , 2010 ) .
progesterone activates signaling pathways associated with neuroprotection like mitogen activated protein kinase , extracellular signal regulated kinase ( mapk / erk ) , or serine / threonine protein kinase akt ( brinton et al .
nilsen and brinton ( 2002 ) showed that prog increased expression of the bcl-2 anti - apoptotic gene , which prevented cell death in rat hippocampal neuronal cultures . in the tbi model in rats , administration of prog increased mrna levels of the bcl-2 and bcl - x(l ) anti - apoptotic genes , and their protein derivatives . on the contrary
, the hormone reduced mrna levels of pro - apoptotic bax and bad genes , as well as their protein products ( yao et al . , 2005 ) .
additionally , the neurosteroid attenuates release of the proapoptotic cytochrome c ( stein and wright , 2010 ) . in cultured hippocampal neurons , prog attenuated lipid peroxidation induced by feso4 and amyloid -peptide , as well as lightened elevation of intracellular ca concentration following -amyloid- or glutamate - induced toxicity ( goodman et al . , 1996 ) .
in rats after tbi , administration of allo decreased apoptotic dna fragmentation and expression of caspase-3 and bax pro - apoptotic proteins . moreover , the neurosteroid improved behavioral outcome of animals similarly to prog ( djebaili et al . , 2004 , 2005 ) .
both neurosteroids reduced production of pro - inflammatory cytokines ( il-1 , tnf- ; he et al . , 2004 ) and enhanced production of the cd55 protein , a complement convertase inhibitor , which was reported to limit inflammatory processes after contusion of the cerebral cortex in rats ( vanlandingham et al . , 2007 ) .
in patients with alzheimer s disease , the level of allo in the temporal cortex was significantly lower than in controls , in contrast to preg and dhea which concentrations were increased .
this may be explained by altered regulation of neurosteroid biosynthetic pathway , blocking allo formation ( naylor et al . , 2010 ) .
similarly , the allo level was found to be decreased in niemann - pick type .
furthermore , allo enhanced myelination and reduced inflammatory processes in brains of npc1(/ ) mice , a genetic model of niemann - pick type c disease ( griffin et al .
, 2004 ; ahmad et al . , 2005 ; mellon et al . , 2008 ; liao et al . ,
( 2001 ) revealed that prog protected dopaminergic neurons against mptp - induced degeneration in rats .
moreover , in mptp mice , prog did not reverse the protective effect of estrogens on dopamine neurons . in methamphetamine model of parkinson s disease , prog used at low doses exerted protective action on striatal dopaminergic neurons in gonadectomized male mice , whereas much higher doses were needed to achieve a beneficial effect in ovariectomized mice ( bourque et al . ,
higher concentrations of prog , allo , and 5-dhp were found in the substantia nigra and nucleus caudate in comparison with other brain areas in female control patients . in patients with parkinson s disease ,
lower concentrations of these neurosteroids than in controls were found in the cerebrospinal fluid ( csf ; luchetti et al . , 2011 ) . during further studies
the authors observed reduced mrna expression of one enzyme synthesizing allo in the substantia nigra , and increased expression of another one in the caudate nucleus .
it seems that disturbed synthesis of allo may result in a dysfunction of endogenous neuroprotective effects ( luchetti et al . , 2011 ) .
similarly , diminished allo concentration and reduced activity of enzymes synthesizing the neurosteroid were found in patients with multiple sclerosis ( luchetti et al . , 2011 ) .
such phenomenon as nmda - induced excitotoxicity in p-19 cell cultures ( pluripotent embryonic cells differentiated into neurons ) was attenuated by allo and dhea , while dheas remained less effective in this respect .
allo prevented the release of cytochrome c to cytoplasm and bax protein translocation to mitochondria .
all these processes are considered to be signs of apoptotic death . since both neurosteroids enhanced expression of gabaa receptor subunits
, their neuroprotective action seems to be mediated by enhanced gaba - ergic neurotransmission ( xilouri and papazafiri , 2006 ) .
reduced levels of this steroid were found in the patient plasma and prefrontal cortex . additionally , elevated concentrations of enzymes metabolizing pregnane steroids were found in brains from early stages of the disease ( luchetti et al . , 2011 ) .
in the mouse model of alzheimer s disease prog treatment improved cognitive functions and reduced hyperphosphorylation of tau protein .
but on the other hand , prog antagonized beneficial effects of estrogens in reducing -amyloid deposits .
it is possible that the sequential therapy with estrogen and prog may bring better results than the treatment with only one hormone ( pike et al . , 2009 ) .
allopregnanolone prevented apoptotic cell death in the human nt2 cell line culture in nmda - induced excitotoxicity ( lockhart et al .
progesterone is widely considered as a pleiotropic drug that can be markedly effective in the treatment of tbi . at present
, more than 180 articles showed protective activity of prog in both experimental animals and humans .
moreover , two independent phase ii clinical trials have revealed that prog group of patients had significantly better survival and functional outcomes than patients given placebo .
nevertheless , in some studies prog was not effective or even worsen the prognosis of animals after tbi or ischemic injury ( murphy et al .
, 2000 ; toung et al . , 2004 ; ciriza et al . , 2006 ; gilmer et al . ,
, medroxyprogesterone acetate , a prog synthetic derivative , may exhibit quite opposite properties in the cns than the parent compound .
medroxyprogesterone did not bring better functional outcome after tbi , moreover , it blocked the expression of bcl-2 gene and estrogen - dependent neuroprotection , increased calcium - induced toxicity ( stein , 2008 ) .
anticonvulsive and antiexcitotoxic properties of prog were widely examined in animal models and clinical studies .
it seems that antiseizure action of this hormone is not mediated by steroid receptor since it occurs quickly ( within minutes ) and is not blocked by the respective receptor antagonist  ru486 .
gabaa receptor activation induces neuronal membrane hyperpolarization and reduces its excitability . in kainic acid - induced seizures in rats
the hormone significantly reduced seizures , mortality , and neuronal death in hippocampus ( hoffman et al . , 2003 ) .
in the same model in mice , allo protected against seizures and reduced neuronal loss in hippocampal fields , while other neurosteroids  negative modulators of gabaa receptor ( dheas , pregs )  remained ineffective or even toxic ( leskiewicz et al . , 1997 ) .
holmes and weber ( 1984 ) tested prog in amygdala - kindled rats and observed kindling inhibition .
secondary generalization of seizures was prevented in immature , but not adult animals . in the same model , prog and allo protected against secondarily generalized seizures , being ineffective or effective only at toxic doses against focal seizures .
on the other hand , 5-dhp inhibited both components of seizures ( lonsdale et al . , 2006 ) .
growing evidence suggests that anticonvulsive and neuroprotective properties of prog are mediated by its metabolites 5-dhp and allo , positive modulators of gabaa receptors ( reddy , 2004 ; ciriza et al . , 2006 ; verrotti et al . , 2010 ; stevens and harden , 2011 ) .
allo itself protected against picrotoxin - induced neuronal cell death ( brinton , 1994 ) .
rhodes and frye ( 2005 ) showed that inhibition of 5-reductase enzyme ( finasteride ) attenuated antiseizure activity of prog and reduced concentration of allo .
( 2003 ) allo showed no significant anticonvulsive action against cocaine - induced kindling in mice , in contrast to isopregnanolon and a representative of negative gabaa modulators  dheas .
some other neurosteroids were reported to inhibit seizures . both prog derivatives : dhp and allo dose - dependently protected the kainate - induced loss of hilar neurons and the induction of vimentin expression in reactive astrocytes ( a sign of neural damage ) in ovariectomized rats ( ciriza et al . , 2004 ) ( table 1 ) .
dehydroepiandrosterone and its sulfate ester ( dheas ) were reported to act as neurotropic or neuroprotective factors , defending neurons against many harmful events , including excitotoxicity .
protective properties of dhea may be related to inhibition of the nmda - induced nitric oxide ( no ) production in hippocampal cells or modulation of the calcium / no signaling pathway .
additionally , dheas was shown to attenuate the destructive action of glutamate and nmda on cerebellar granule cells in rats .
protective effects of both dhea and dheas can be realized through preventing the mitochondria against intracellular ca overload ( mao and barger , 1998 ) .
time- and dose - dependent neuroprotective action of dhea was documented in the in vivo model of global cerebral ischemia in rats .
administration of dhea at the dose of 20  mg / kg during 348  h after ischemia reduced neuronal death in the hippocampal ca1 region and ameliorated ischemia - induced deficits in spatial learning . whereas , the treatment of dhea ( 20  mg / kg , 1  h before or after ischemia ) may intensify the ischemia - induced neuronal damage and learning failure .
kg ( for 15  days before induction of ischemia ) led to more pronounced neuroprotective effects and reduced hippocampal ca1 neuronal injury ( li et al . , 2001 ) .
these study may suggest that dhea , dependently on time of treatment , exhibits a dual action  it may be either neurotoxic or neuroprotective , depending on the time of treatment initiation and duration ( li et al . , 2009 ) .
dhea sulfate significantly inhibited the amplitude of persistent sodium currents , and this result was canceled by the gi protein inhibitor , protein kinase c inhibitor , sigma-1 receptor blockers , but not by the protein kinase a inhibitor .
these results suggest that dheas may protect neurons against ischemia by activation of sigma-1 receptor ( cheng et al . , 2008 ) .
the neurosteroid exhibited a preventive effect when it was administered 5  min , but not 30  min after ischemia .
the beneficial effect of dhea was reversed by bicuculline , the gabaa antagonist , which indicates gaba - ergic mechanism of the neurosteroid action ( lapchak et al . , 2000 ) .
however , it should be remembered that dhea administered during ischemia may be also neurotoxic . according kimonides et al .
( 1998 ) , dhea showed a dose - dependent neuroprotective effect against glutamate excitotoxicity mediated by nmda receptors ( in vivo and in vitro ) or evoked by ampa / ka receptor agonists ( in vitro ) .
for instance , the neurosteroid prevented hippocampal ca1/2 neurons against toxicity induced by nmda infusions . thus , decreased level of dhea in aging people may increase vulnerability of the brain to such a damage .
age - related declines of neurosteroids have been postulated to play a role in the pathogenesis of neurodegenerative diseases ( hillen et al . , 2000 ; brown et al . , 2003 ; naylor et al . , 2008 ) .
interestingly , dhea - induced protection against ka - induced excitotoxicity in hippocampal hilar neurons was attenuated by letrozole , an aromatase inhibitor ( veiga et al . , 2003 ) .
taking this into consideration , neuroprotective effects of dhea in the hippocampus can be mediated by estradiol ( azcoitia et al . , 1998 ;
it should be stressed that expression of aromatase in reactive glial cells is induced after brain injury ( garcia - segura et al . , 2003 ) .
some results suggest that dheas may be a negative modulator of gabaa receptors . in the study of czlonkowska et al .
( 2000 ) , intracerebroventricularly administered dheas induced seizures in a dose - dependent manner .
but on the other hand , dheas ( 25  mg / kg , i.p . )
significantly increased the dose of nmda necessary to induce clonic convulsions in mice , indicating that the neurosteroids can protect mice against nmda - induced seizures and mortality ( budziszewska et al . , 1998 ) .
the antiseizure effect of dhea was also proved in the iron - induced model of posttraumatic epilepsy in rats .
dhea at the dose of 30  mg / kg / day prevented epileptiform electrophysiological activity and attenuated cognitive defects produced by epileptic activity ( mishra et al . , 2010 ) .
this raises the possibility that exogenously administered neurosteroids or their synthetic analogs could be clinically effective as antiepileptogenic drugs , e.g. , after tbi ( biagini et al . , 2006 ) .
possibly , these drugs may create a promising novel therapeutic avenue for the treatment of this dysfunction in humans .
the neurosteroid accelerated axonal regeneration ( ayhan et al . , 2003 ) and increased the number of myelinated fibers and fiber diameters after sciatic nerve transection in rats ( gudemez et al . , 2002 ) .
according to frye and reed ( 1998 ) , a 3-diol metabolite of another androgen  testosterone 
moreover , the neurosteroid reduced hippocampal cell death and improved animal performance in the morris water maze . interestingly ,
this action was inhibited by gabaa receptor blockade , therefore it is not clear whether the action of 3-diol is due to enhanced gaba - ergic neurotransmission or to increased estrogen concentration ( table 1 ) .
although there is no literature data on neuroprotective properties of deoxycorticosterone doc ) and its derivative allotetrahydrodeoxycorticosterone ( thdoc ) , the two neurosteroids exhibited anticonvulsive effects in some experimental studies .
for instance , thdoc protected against convulsions induced by the gabaa receptor antagonists , like picrotoxin , pentylenetetrazole , or bicuculline , and the glutamate receptor agonists , such as kainic acid or nmda .
the neurosteroid , administered at relatively high doses , showed also the anticonvulsive action in the rat model of amygdala kindling and the maximal electroshock test in mice . in human studies , decreased serum level of thdoc was found in women with catamenial epilepsy , which may indicate a role of this neurosteroid in the pathophysiology of perimenstrual seizures .
the antiseizure effect of thdoc seems to depend on positive allosteric modulation of gabaa receptor ( reddy , 2009 ) ( table 1 ) .
therefore some modified derivatives were synthesized in order to select drugs , which are not so rapidly metabolized .
neurosteroid analogs offered mainly a broad spectrum of anticonvulsive activity in different experimental seizure models . therefore , this group of neurosteroids are mostly considered as a novel class of antiepileptic agents .
ganaxolone ( gnx , 3-hydroxy-3-methyl-5-prengan-20-one ) is the 3-methylated analog of allo . as the parent compound , gnx is a positive allosteric modulator of gabaa receptors and increases chloride channel permeability within the gabaa  benzodiazepine receptor  chloride ionophore complex ( carter et al . , 1997 ;
the neurosteroid exhibited effectiveness in a broad range of animal models of epilepsy , including convulsions induced by pentylenetetrazole , bicuculline , fluorothyl , cocaine , aminophylline , as well as in pentylenetetrazole kindling , amygdala kindling , and 6  hz electrical stimulation ( gasior et al .
, 2000 ; ungard et al . , 2000 ; reddy and rogawski , 2000a , b ; kaminski et al . , 2004 ) .
powerful antiseizure effects of gnx in the amygdala - kindled model in mice strongly support the utility of this substance in the treatment of temporal lobe epilepsy ( reddy and rogawski , 2010 ) .
however , most data on this neurosteroid was obtained in preclinical models of catamenial epilepsy . according to reddy and rogawski ( 2009 ) , gnx treatment ( 7  mg / kg , sc ) significantly reduced the frequency of spontaneous seizures in rats .
these results raise the possibility that gnx might provide a specific treatment for catamenial epilepsy in humans . on the other hand , this allo analog proved to be ineffective against nmda- and strychnine - induced seizures in mice ( carter et al . , 1997 ; gasior et al . , 1997 )
, gnx was shown to be well tolerated in adults and children . in early phase ii studies
, gnx was found to be effective in adult patients with partial - onset seizures and in epileptic children with history of infantile spasms .
currently , further investigations are conducted in infants with newly diagnosed infantile spasms , women with catamenial epilepsy , and adults with refractory partial - onset seizures ( rogawski and reddy , 2004 ) .
it was recently reported that the pretreatment with a new synthesized analog of allo , 3-hydroxy-21,22-oxido-21-homo-5-pregnan-20-on ( hohp ) , suppressed generalized tonic 
clonic seizures in pentylenetetrazol - induced seizures in mice , and efficacy of this analog resembled that of gnx ( mare et al . , 2010 ) .
two synthetic neurosteroids , minaxolone ( 2,3,5,11)-11-(dimethylamino)-2-(ethoxy-3-hydroxypregnan-20-one ) , and alfaxalone ( 5-pregnan-3-ol-11,20-dione ) seem to be effective positive allosteric modulators of the 1 glycine receptor ( maksay and biro , 2002 ; weir et al .
alphaxalone showed , moreover , a moderate anticonvulsive activity in the rat model of kindling and maximal electroshock in mice ( rogawski and reddy , 2004 ) .
another synthetic neurosteroid , co 2 - 1068 ( 3-(4acetylphenyl)ethynyl-3,21-dihydroxy-5-20-one-21-hemisuccinate ) was re - ported to be effective against pentylenetetrazole- , nmda- , and cocaine - induced seizures in mice ( gasior et al . , 1997 ) .
so far , only fluasterone ( dhef ) , a novel dhea analog , was considered as a candidate for a drug used in the treatment of tbi in humans .
possible dhef mechanisms of action are still unclear and discussed . according to malik et al .
( 2003 ) , this neurosteroid markedly inhibited synthesis of prostaglandin ( pge2 ) and interleukin-1a - induced cyclooxygenase-2 ( cox2 ) in cultures of rat mesangial , but not cortical or hippocampal cells ( malik et al . , 2003 ) ( table 1 ) .
these natural and synthetic compounds attenuate the excitotoxicity , brain edema , inflammatory processes , oxidative stress , and neural degeneration .
promising results of preclinical studies directed scientist attention toward possible profits of neurosteroid treatment in a wide range of diseases , especially the brain and spinal cord injury , stroke , parkinson s and alzheimer s diseases , or epilepsy . unfortunately , therapeutic application of natural neurosteroids was significantly limited by its rapid biotransformation .
only synthetic analogs of these substances , particularly ganaxolone or 3-ol-5-pregnan-20-one , can be considered as potential anticonvulsive drugs .
this gives a real hope that neurosteroids can be also used as effective neuroprotective drugs .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 neurosteroids were initially defined as steroid hormones locally synthesized within the nervous tissue . 
 subsequently , they were described as steroid hormone derivatives that devoid hormonal action but still affect neuronal excitability through modulation of ionotropic receptors . 
 neurosteroids are further subdivided into natural ( produced in the brain ) and synthetic . 
 some authors distinguish between hormonal and regular neurosteroids in the group of natural ones . 
 the latter group , including hormone metabolites like allopregnanolone or tetrahydrodeoxycorticosterone , is devoid of hormonal activity . 
 both hormones and their derivatives share , however , most of the physiological functions . 
 it is usually very difficult to distinguish the effects of hormones and their metabolites . 
 all these substances may influence seizure phenomena and exhibit neuroprotective effects . 
 neuroprotection offered by steroid hormones may be realized in both genomic and non - genomic mechanisms and involve regulation of the pro- and anti - apoptotic factors expression , intracellular signaling pathways , neurotransmission , oxidative , and inflammatory processes . 
 since regular neurosteroids show no affinity for steroid receptors , they may act only in a non - genomic mode . 
 multiple studies have been conducted so far to show efficacy of neurosteroids in the treatment of the central and peripheral nervous system injury , ischemia , neurodegenerative diseases , or seizures . in this review 
 we focused primarily on neurosteroid mechanisms of action and their role in the process of neurodegeneration . 
 most of the data refers to results obtained in experimental studies . 
 however , it should be realized that knowledge about neuroactive steroids remains still incomplete and requires confirmation in clinical conditions . 
Introduction
Pregnenolone
Progesterone and Derivatives
Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate Ester
Deoxycorticosterone and Allotetrahydrodeoxycorticosterone
Synthetic Neurosteroids
Conclusion
Conflict of Interest Statement