Translocator Protein Formerly Known As Peripheral Benzodiazepine Receptor Biology Essay


The translocator protein (18kDa) (TSPO) formerly known as the peripheral benzodiazepine receptor. One of the proteins which may mediate MTP is TSPO but its physiological role remains unclear except for in steroidogenesis specific tissues. This literary review is going to concentrate on TSPO mediated cholesterol transport, mitochondrial permeability regulation, cardioprotective and neuroprotective function. on… by analysisng information obtained about TSPO through the ffects its ligands

Subcellular localisation and structure of TSPO

The TSPO receptor is enriched in the mitochondria at inner mitochondrial - outer mitochondrial membrane (OMM) contact sites [1]. TSPO was first isolated in a ternary receptor complex with voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) [1]. This multimeric complex has been observed to encompass 4-16 TSPO 18kDa receptors which can transition between monomeric to polymeric states in response to signals such as reactive oxygen species to alter their affinity to specific ligands [2]. In freeze fractured proteoliposomes, 50% of TSPO receptors were present as dimers under physiological conditions [2].

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Several lines of evidence have proposed a mammalian TSPO structural arrangement which allows the binding as well as transport of certain ligands. Firstly, hydropathy experiments have shown a pentahelical TSPO structure featuring five transmembrane (TM) α-helical domains that completely traverse the outer mitochondrial membrane [3]. Circular dichroism and NMR experiments have given further details of the unstable TSPO tertiary fold made up of 5 independently folded TM domains which become stabilized upon drug ligand binding [4]. Furthermore, the TSPO primary sequence of 169 amino acids has 80% homology between species, the structure of which is highly conserved in nature [5]. Therefore, cryo-EM structures of the bacterial homologue tryptophan rich sensory protein (TspO), a dimer of five α helices packed into a ten helix bundle supports previous structural and polymerisation evidence [6].

Cholesterol transport and steroid biosynthesis

TSPO has a high affinity for cholesterol

Steroidogenesis is the process by which steroids are produced from cholesterol. The most established and best documented role of TSPO is cholesterol transport which has been demonstrated using various experimental techniques. Cholesterol is a high affinity ligand for TSPO as well as the sole precursor molecule for steroid biosynthesis. Cholesterol is transported into the mitochondria by binding a cholesterol recognition amino acid consensus (CRAC) domain on TSPO [7]. The model of TSPO cholesterol binding was illustrated by isolating a TSPO recombinant protein which demonstrated its ability to bind cholesterol at the carboxyl 150-156 TSPO amino acids [2]. A direct role for TSPO in cholesterol transport was presented using SV-3T3 fibroblasts transfected with pCMV523 vectors to express mammalian TSPO which caused an increase in cholesterol uptake directly linked to the increase in TSPO receptors present in the cell [8]. The effect of cholesterol transport exerted by TSPO ligands was shown to be specific to the OMM as TSPO ligand stimulated translocation of cholesterol into the mitochondria was observed in mitochondria and not in mitoplasts [8].

The current literature suggests stimulatory or inhibitory effects on cholesterol transport can be exerted by different TSPO ligands as well as the precise polymeric conformation of the TSPO receptor. Flunitrazepam, an antagonist TSPO ligand has been shown to inhibit the ability of TSPO to bind cholesterol transport by binding to TSPO sites other than the cholesterol binding CRAC domain [8]. In contrast, enhanced cholesterol binding rate and uptake in a ligand dependent manner was observed by adding the TSPO ligand PK1110 to the dimeric state of TSPO [2]. However the stimulatory effect TSPO ligands induce on cholesterol transport has not been observed to be an additive stimulatory effect to hormones and cAMP [8].

TSPO and the transduceosome; the mechanism of cholesterol transport into the matrix

A 240kDa mitochondrial complex consisting of TSPO, PKARIα, PKARIα associated protein 7 (PAP7), Steroidogenic acute regulatory protein (STAR) and VDAC was identified by immunoblot analysis and is now better known as the transduceosome [9]. This complex facilitates the transport of cholesterol from a cytosolic donor or an intracellular store through TSPO and VDAC contact sites in the OMM to the inner mitochondrial membrane (IMM) (Figure 1 ) [9]. The formation of this transduceosome is initiated by hormonal stimulation which activates adenylate cyclase to synthesize cAMP [9]. cAMP stimulates specific cell surface receptors in a number of organelles such as the Golgi and mitochondria to promote the traffic of cholesterol to the IMM [7]. In a cAMP dependent manner, PAP7 and PKARIα are transported from the trans Golgi to the mitochondria whilst STAR is synthesized in the cytoplasm [9] [7]. At the outer mitochondrial membrane, STAR interacts with the mitochondrial VDAC to exert its effects in a phosphorylation-dependent manner by the cAMP dependent protein kinase (PKA) which also phosphorylates TSPO [7]. Hormone induced elevated levels of cAMP causes proteins such as TSPO to redistribute so that PAP7 and PKARIα can interact with TSPO [9]. At the mitochondria, PAP7 transduces the elevated cAMP concentration signal to the rest of the transduceosome by bridging PKARIα and TSPO which in combination with the arrival of STAR form a STAR-PKARIα-PAP7-TSPO complex to transport cholesterol [9]. TSPO is responsible for transporting cholesterol through the OMM and IMM into the matrix, the rate determining step [8]. As cholesterol reaches the mitochondrial matrix it can interact with the P450 enzyme CYP11A1 which converts cholesterol to pregnenolone [7]. Pregnenolone can then leave the mitochondria so it can be converted into progesterone by the endoplasmic reticulum resident enzyme 3β-hydroxysteroid dehydrogenase [10].

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Figure 1 The transduceosome complex facilitates steroidogenesis. Adapted from [9]

After hormonal stimulation, the transduceosome complex is formed from the basal protein-protein interactions of TSPO, VDAC and ANT. TSPO, PAP7 and VDAC recruit PKA-RIα and binds to PAP7.High levels of cAMP binds to the regulatory subunits of PKA-RIα which causes the release of the catalytic subunits and subsequent phosphorylation of STAR. The transduceosome in the presence of DBI transports cholesterol to the IMM. CYP11A1 is present in the IMM and converts cholesterol into pregnenolone [11]

Mitochondrial Permeability transition


Mitochondrial permeability transition (mPT) is characterised by a sudden increase in the permeability of the IMM due to the opening of a nonspecific mitochondrial permeability transition pore (mPTP) in response to factors such as elevated Ca2+ matrix levels or oxidative stress [12-13]. When the IMM becomes permeable to molecules smaller than 1.5 kDa, ions and water enter the matrix and causes swelling, OMM rupture and subsequent release of proapoptotic factors such as cytochrome c and apoptosis inducing factor (AIF) into the cytosol [14].

mPTP identity

The importance of the mPT in determining the fate of cell death would require an understanding of the components which form and regulate the pore, however, to date, the molecular identity of the mPTP remains uncertain [15-16]. A generally accepted mPTP opening model encompasses the peptidyl-prolyl cis-trans isomerase activity of cyclophilin-D (CyP-D), a mitochondrial matrix protein, inducing a calcium dependent conformational change on ANT which allows pore formation [17]. The role of cyclophilin D in facilitating the mPTP opening has been demonstrated in transgenic cyclophilin D Ppif knockout mice which were protected from Ca2+ and H2O2 induced mitochondrial membrane permeabilization in comparison to control mice by being more resistant to Ca2+ overload [18]. The importance of ANT in mPTP opening was also shown by inhibiting mPTP opening by the addition of matrix adenine nucleotides in the m conformation of ANT which occurred in a CSA independent manner [17].

However it is unlikely that cyclophilin D and ANT are components of the pore itself as under strong enough conditions, mPTP opening can still occur in the absence of these two components [18-19]. Therefore, recent literature has moved towards investigating whether the mitochondrial phosphate carrier (PiC) is the pore forming component. Coimmunoprecipitation between PiC and ANT demonstrated a close association between the two components, both of which can also bind modulators of mPTP opening such as phenylarsine oxide [15]. However the critical role of PiC in mPTP formation has not been investigated by knockout experiments because this results in cell death.

The latest model of mPTP opening therefore involves calcium induced pore formation facilitated by CyP-D which induces a conformational change on PiC enhanced by the close association of ANT [15]. This overall mechanism can be regulated by components of the OMM such as VDAC and TSPO [20].

Association of TSPO with mPTP

The biochemical co-purification of TSPO with ANT and VDAC provided the first insight into a possible association between TSPO and proteins which comprise an active role in the mPTP complex [1]. Since then, TSPO ligands have been shown to activate or inhibit mPTP opening. More convincingly, a direct involvement of TSPO in mPTP opening was observed in specific anti TSPO antibody delayed Ca2+ induced PTP opening which also suggests that TSPO is most likely in a pre activated form possibly as a result of binding endogenous ligands or already being polymerised [21].

However, mPT can occur in the absence of ANT, VDAC and the OMM (containing TSPO) in mitoplasts which questions the current model in which the mPTP spans both the OMM and IMM[12]. This also implies the OMM exhibits a regulatory rather than fundamental role in pore opening possibly through proteins such as TSPO which are also in contact with the IMM.

Figure 2

MPTP complex structure. Copied from [16, 22]

Regulation of the mPTP by TSPO

TSPO may have a crucial role in determining cell death fate either by apoptosis or necrosis as mPTP opening is a key initiator of apoptosis through the release of proapoptotic factors, furthermore once opened, if the mPTP can be closed again it can prevent necrotic cell death [13].

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The effect TSPO exerts on the mPTP is not fully understood, however three main roles for the TSPO have been suggested; ligand binding, ligand transport and phosphorylation mediated MPTP regulation. Firstly, regulation of the mPTP can be exerted by different TSPO ligands which can induce or inhibit mPTP opening [21]. The well characterised PK11195 TSPO ligand induces mPTP opening in isolated cardiac mitochondria consistent with mitochondrial swelling, oxidative phosphorylation uncoupling and cytochrome c loss in a calcium independent and cyclosporin A sensitive manner [14]. In contrast the TSPO ligand Ro5-4864 delayed Ca2+ induced mPTP opening and inhibited mPT [23]. However there are contradictions in the literature on the consistent effect TSPO specific ligands have on mitochondrial pore opening. The same ligand used in different cell types can have opposing effects on mPTP opening as seen in rat cardiac mitochondria where Ro5-4864 induced mPT without any calcium addition [24]. It is possible that the effect TSPO ligands have on the mPTP through the TSPO is ligand and cell type specific. However, by looking thoroughly through the literature it has been noticed that when TSPO ligands such as PK11195 and Ro5-4864 are used in concentrations close to their affinity for TSPO they exert mPTP closing. High concentrations of these TSPO ligands may be exerting proapoptotic effects via non TSPO mediated mechanisms when used at higher concentrations[25].

TSPO ligand

Cell type

Effect on mPT



induced mPT


inhibited mPT



induced mPT

Secondly TSPO can regulate the mPTP by facilitating the diffusion of molecules to the IMM or matrix where they can exert their mPTP-dependent function such as TSPO facilitated porphyrin transport which inhibits the mPTP from opening [12].

A third possible way in which TSPO can regulate the mPTP could be mediated by phosphorylation of phosphoproteins associated with the mPTP, anti TSPO was shown to delay mPTP opening and therefore the increase in protein phosphorylation observed upon mPTP opening is not observed [21].

Cardio protective properties of TSPO

Ischemia reperfusion injury (see review [22])

Myocardial ischaemia is characterized as the deprivation of blood and oxygen supply to the heart which commonly occurs in diseases such as atherosclerosis, myocardial infarction or during heart surgery. This condition leads to a decrease in mitochondrial oxidative phosphorylation, pH, ATP and thus ATP dependent repair pathways which can lead to necrotic cell death. Short term ischaemia can be reversible, however, upon reperfusion a burst of ROS from the electron transport chain and xanthine oxidase increase cell damage which causes necrotic cell death although apoptosis is present to a lesser extent. The increased damage reperfusion exerts on ischaemia is called ischaemia reperfusion injury. The conditions which induce mPTP opening such as Ca2+ and ROS overload are customary in myocardial ischaemia-reperfusion injury which is further exaggerated by the loss of adenine nucleotides and increase of Pi during ischaemia. Oxidative stress and neutrophil activation are two other underpinning processes of ischaemia reperfusion injury [26] which create an inflammatory response and increases the damage to the surrounding heart cells.

Evidence supporting the mPTP as a cardio protective target

To reduce cell death from ischaemia reperfusion injury, the proton motive force must be recreated across the mitochondria by closing the mPTP. Therefore the mPTP is a target for cardio protection by limiting mitochondrial membrane permeabilization [23]. Although the mPTP identity is not fully understood, the components currently believed to be part of the pore have been targeted on myocardial cells exposed to ischaemic and reperfusion conditions to investigate possible cardioprotective effects. Infarct size in Cyclophilin D deficient knockout mice subjected to cardiac ischaemia reperfusion injury were found to have 40% reduced infarct size in comparison to wild type mice[18]. The effectiveness of suppressing the mPTP as a cardio protective technique was also investigated with known drug inhibitors of the mPTP such as cyclosporin A which improved cell survival in human atrial tissue at the onset of reoxygenation from 62% to 91% [27]. This technique has also been shown to be cardio protective at the time of reperfusion in human cardiac muscle by using cyclosporine A to reduce necrotic cell death [27]. Although cyclosporine does protect from reperfusion by inhibiting opening of the mPTP it has harmful side effects. The search for a new cardio protective drug which inhibits opening of the mPTP without any harmful side effects is a key strategy to treat ischaemia reperfusion injury.

TSPO ligands reduces mPTP opening in the heart

Although TSPO is primarily present in steroid synthesisisng tissues, it is also present in non steroidogenic tissues such as the heart [23]. Certain TSPO ligands have been observed to inhibit mPTP opening when used close to their nano molar affinity for TSPO. Therefore, the regulatory role of TSPO on the mPTP could theoretically be exploited using TSPO drug ligands during ischaemia reperfusion injury to increase cell survival. The TSPO ligand Ro5-4864 was observed to reduce myocardial infarct size and protect against ischaemic and reperfusion insults by inhibiting mitochondrial outer membrane polarisation [23].

The cardioprotective effects Ro5-4864 exerts are proposed to be due to reorganising the balance of Bcl-2 family proteins to promote cell survival and reduce the release of intermembrane proapoptotic proteins such as cytochrome c and AIF [23]. However, the above compound binds to a nonspecific TSPO site which affects steroidogenesis [20] and appears to prevent apoptotic cell death rather than necrotic cell death, the most prevalent during ischaemia reperfusion injury.

Unlike the above TSPO ligand, TRO40303 binds specifically to the cholesterol site on TSPO and although the ligand competes with cholesterol, clinical trials suggest steroidogenesis is not affected possibly due to the lower affinity of TRO40303 for TSPO than cholesterol [28].

TRO40303 reduced cell mortality by 38% upon reperfusion by delaying mPTP opening as seen by a reduction in AIF release upon Ca2+ stimulation. However, in comparison to CsA, the inhibitory effect TRO40303 exerts on mPTP opening may be a combination of two cardioprotective properties; inhibiting mPTP opening and reducing ROS production [28].

The above TSPO ligands which maintain the mitochondrial membrane potential, integrity and protect the heart from ischaemia reperfusion injury are strong cardioprotective therapeutic targets.

However due to the close interaction between TSPO, components of the mPTP and other mitochondrial proteins in the OMM it may be that the above effects cause a change in the interaction between all the proteins and may therefore not necessarily be specific to TSPO.

TSPO Decreases inflammatory response after ischaemia reperfusion injury

The majority of cell death in cardiac ischaemia reperfusion injury occurs by necrosis. Neutrophils are recruited to the damaged area, create an inflammatory response and further damage to the heart tissue [22]. There is evidence to suggest TSPO ligands can be cardio protective by decreasing the damage caused by necrosis mediated inflammatory reponses, although this process is not fully understood.

It has been proposed that TSPO ligands can inhibit the action of inflammatory cells and therefore reduce inflammatory responses by a mechanism which is possibly regulated by glucocorticoid synthesis [29]. Furthermore, a strong link between TSPO expression and inflammation caused by ischaemia reperfusion was also shown in monocytes and B/T lymphocytes [26].

However, reducing inflammation upon TSPO ligand administration is most likely an additive effect to the cardioprotective properties of targeting TSPO as with no contribution from platelets or neutrophils in isolated fluid-perfused hearts, infarct size was observed to reduce with SSR180575 [30].

TSPO ligands increases the activity of mitochondrial electron transport chain complex I and complex III

TSPO receptors are present in the mitochondrial membrane in close contact to the components of the electron transport chain and therefore TSPO is suggested to have a role within mitochondrial respiration and oxygen homeostasis[31]. ROS were used to dissipate the membrane potential and stop oxidative phosphorylation, both of which were preserved in the presence of the TSPO ligand SSR180575 [30]. Subsequently, this was shown to decrease ischaemic and reperfusion induced infarct size and contractile dysfunction whilst increasing cardiac recovery in isolated rabbit hearts [30]. How TSPO ligands preserve the activity of respiratory chain components is largely understood, however in a recent paper, the TSPO ligand 4'-chlorodiazepam has given light into a possible mechanism. NADH dehydrogenase (complex I) and ubiquinone-cytochrome b in complex II are respiratory chain ROS causative agents under decreased oxidative capacity conditions such as in reperfusion [32]. 4'-chlorodiazepam was shown to increase the activity of both complex I and complex II which leads to reduced ROS generation and maintenance of the mitochondrial electron transport chain [32].

Involvement of TSPO in ROS

In ischaemia reperfusion injury, reactive oxygen species (ROS) are produced by the mitochondria and initiate the triggering events which have both a direct and indirect effect on cell death [33].

TSPO has been proposed to mediate apoptotic and necrotic cell death signalling pathways after ischaemia reperfusion [33] and therefore whether TSPO exerts this protective effect by regulating ROS has been investigated. Treatment with the irreversible TSPO ligand SSR180575 was shown to prevent in vivo apoptosis after ischaemia reperfusion by reducing oxidative stress possibly by protecting the mitochondria from exogenous ROS and by regulation the mitochondrial generation of ROS [33]. TSPO may therefore act as an oxygen sensor which in response to oxygen it preserves the mPT and therefore also prevents the release of pro-apoptotic factors and thus apoptosis[31]. In rats an increase in oxidative stress was accompanied by a decrease in TSPO ligand binding in the liver and aorta to compensate for the oxidative stress induced by the high fat and cholesterol diet [34]. A reduction in TSPO expression may compensate for the increased oxidative stress by reducing the ROS being generated otherwise it could be that TSPO is responding to the inflammatory response caused by the diet [34]. Xanthine oxidase and NADPH oxidase are key producers of ROS in cardiac tissue when the activities of these are increased during reperfusion [32]. 4'-chlorodiazepam decreased the activity of xanthine oxidase and NADPH oxidase and thus reduced ROS levels.

Figure 3

Neuroprotective properties of TSPO

Within the brain TSPO is mostly present in the mitochondria of cerebellar and cortical neurons as well as glial and neuroblastoma cells [35]. Following brain injury such as stroke, hypoglycaemia or traumatic brain injury a range of cellular signals propagate a cell death response [36]. These include the dissipation of the transmembrane potential needed for oxidative phosphorylation and the permeabilization of the OMM which results in the release of cytochrome c and caspase activation [36]. Mitochondrial damage is a common pathway between these events following neurotrauma{Papadopoulos, 2009 #15}. Furthermore TSPO ligands have shown to protect from the above effects and also appear to have additional additional neuroprotective mechanisms by promoting neuronal survival by glial proliferation or by producing neurotropic factors [35].

TSPO neurological expression

Normal TSPO expression levels in the brain are low but these are up regulated where damage has occurred [37].The increased levels of TSPO receptors have been shown to help the functional recovery of these cells, however the exact mechanism by which TSPO exerts this effect is largely unknown [38]. When traumatic brain damage was induced using Kianic acid in rats, TSPO expression was observed to increase fivefold in the hippocampus [31]. TSPO density may be viewed to increase due to microglia invasion at the site of injury which themselves express large numbers of TSPO [10]. Alternatively, microglia could be increasing the number of TSPO receptors within their cells. Regardless of the mechanism, TSPO ligands can be used as sensitive neuroimaging markers for brain damage in vivo by using techniques such as single photon emission computed tomography (SPECT) [37].

TSPO reduces apoptosis

Via its interactions with the mPTP, TSPO has been shown to be involved in the regulation of apoptosis by impeding the release of cytochrome c has been investigated in brain cells after stroke ischemic damage [21]. For many years, the neuro-protective effect of diazepam on the brain was believed to be hypothermic and GABAA receptor mediated. However, diazepam has been showne to suppress stress induced cytochrome c release and therefore apoptosis by targeting TSPO [39].

Pre-treatment with Ro5-4864 increased the number of surviving neurons and was observed to decrease caspase 3 and 9 activity which is dependent on cytochrome c release[36]. Cholest-4-en-3-one, oxime (TRO19622) was identified as a neuroprotective drug for Amyotrophic lateral sclerosis and stopped the progressive cell death of cortical and spinal motor neurons by reducing cytochrome c release. [40] TSPO ligands have have been shown to not only reduce cell death but also encourage neuronal renewal as observed with TRO19622 which promoted neuronal outgrowth, branching and overall higher neuronal density [40]. However, TRO19622 binds to both TSPO and VDAC, therefore it is possible that the drug exerts its effects through other mechanisms apart from those associated with TSPO [40].

Another mechanism by which TSPO may regulate apoptosis is by controlling the expression of proapoptotic Bax and anti-apoptotic bcl-2 proteins. Overexpression of bcl2 impedes on mPTP opening and therefore stops the progression of the apoptotic pathway[33].

As the level of cerebral oxygenation increases the levels of TSPO expression was observed to increase proportianaly and decrease the levels of apoptotic cells. [31]. This suggests that TSPO may also confer an oxygen dependent regulation on apoptosis.

TSPO ligands induce apoptosis

On the other hand there is evidence suggesting a pro apoptotic function of TSPO can be induced with certain ligands. Colchine is a microtubule disturbing drug which induces apoptosis, upon the addition of TSPO ligands such as PK11195 , Ro5-4864 and Diazepam, cyt c and AIF release was amplified and thus an increase in caspase 3 activity was observed [35]. The concentrations of TSPO ligands required to induce apoptosis by mPTP opening were in the micro molar range when these have nano molar affinities to TSPO, therefore it is unclear whether this is a direct effect on TSPO [35]. It is possible that TSPO ligands can exert pro-apoptotic activity in synergy with pro apoptotic agents such as Colchine but not on their own{Papadopoulos, 2009 #15}.

Figure 4

TSPO is neuroprotective via steroid biosynthesis

TSPO ligands which allow the translocation of cholesterol into the matrix exert neuroprotective qualities which other TSPO ligands are not capable of achieving. In the same experiment Ro5-4864 prevented kianic acid induced loss of neurons and hippocampal damagewhereas PK11195 which binds to a different site in the TSPO receptor and does not translocate cholesterol into the mitochondrial matrix in nervous tissue did not. This suggests that Ro5-4864 may facilitate neuronal recovery because it allows TSPO to transport cholesterol to initiate steroidogenesis [38]. Similarly, SSR180575 enhances pregnenolone concentration in the brain and possibly activates neuroprotective steroid biosynthesis in microglial cells which can increase neuronal protection, survival and repair [10]. SSR180575 was observed to penetrate the brain well and have a long effective duration of up to 12 hours of action at doses which occupied 50 to 70% of TSPO receptors in vivo studies[10]. The neuroprotective effects of SSR180575 were further investigated ( NCT00502515) in patients with diabetic and mild peripheral neuropathy to assess the effect of the TSPO ligand on the rate of nerve regenerations. The steroid metabolic pathways involved in decreasing motor neuron death have not been identified nor how they inhibit the release of anti-apoptotic factors through the mPTP which inhibits apoptosis in glial or neuronal cells [10].

Collectively the current evidence supports a model on which stimulating the formation of neurosteroids such as pregnenolone by glia cells in response to TSPO ligandsin vivo induces neurogenesis. Info


Under physiological conditions TSPO is most likely involved in the transport of cholesterol and protoporphyrin species, however under stressful conditions such as CA2+ overload, TSPO rearrangement, often dimerization is promoted to enhance mPTP opening and different TSPO agonists or antagonists compete with each other to regulate this effect[21].

The protective properties of TSPO ligands seen in cells correlate with the effects preventing the mPTP from opening have.

When reviewing all the literature mentioned above it is most likely that TSPO exert their neuroprotective properties in 2 ways. They promote the recovery of neuronal cells by stimulating glial production of neurosteroids such as pregnenolone. They also reduce the number of cells which die by reducing mPTP opening upon brain injury which would otherwise promote apoptosis. Most of our understanding of the function of TSPO has come from investigating the effects TSPO ligands however these may not necessarily reflect the role of TSPO and the effects may even be caused by TSPO independent pathways[21].