Task-based functional magnetic resonance imaging (tfMRI) has developed as a common alternative in epilepsy surgery to the intracarotid amobarbital procedure, also known as the Wada procedure. Prior studies have implicated tfMRI as a comparable predictor of postsurgical cognitive outcomes. However, the predictive validity of tfMRI has not been established. This preregistered systematic review and meta-analysis (CRD42020183563) synthesizes the literature predicting postsurgical cognitive outcomes in temporal lobe epilepsy (TLE) using tfMRI. The PubMed and PsycINFO literature databases were queried for English-language articles published between January 1, 2009 and December 31, 2020 associating tfMRI laterality indices or symmetry of task activation with outcomes in TLE. Their references were reviewed for additional relevant literature, and unpublished data from our center were incorporated. Nineteen studies were included in the meta-analysis. tfMRI studies predicted postsurgical cognitive outcomes in left TLE (ρ ̂ $$ \hat{\rho} $$ = -.27, 95% confidence interval [CI] = -.32 to -.23) but not right TLE (ρ ̂ $$ \hat{\rho} $$ = -.02, 95% CI = -.08 to .03). Among studies of left TLE, language tfMRI studies were more robustly predictive of postsurgical cognitive outcomes (ρ ̂ $$ \hat{\rho} $$ = -.27, 95% CI = -.33 to -.20) than memory tfMRI studies (ρ ̂ $$ \hat{\rho} $$ = -.27, 95% CI = -.43 to -.11). Further moderation by cognitive outcome domain indicated language tfMRI predicted confrontation naming (ρ ̂ $$ \hat{\rho} $$ = -.32, 95% CI = -.41 to -.22) and verbal memory (ρ ̂ $$ \hat{\rho} $$ = -.26, 95% CI = -.35 to -.17) outcomes, whereas memory tfMRI forecasted only verbal memory outcomes (ρ ̂ $$ \hat{\rho} $$ = -.37, 95% CI = -.57 to -.18). Surgery type, birth sex, level of education, age at onset, disease duration, and hemispheric language dominance moderated study outcomes. Sensitivity analyses suggested the interval of postsurgical follow-up, and reporting and methodological practices influenced study outcomes as well. These findings intimate tfMRI is a modest predictor of outcomes in left TLE that should be considered in the context of a larger surgical workup.

Objective: Atypical patterns of language lateralization due to early reorganizational processes constitute a challenge in the pre-surgical evaluation of patients with pharmaco-resistant epilepsy. There is no consensus on an optimal analysis method used for the identification of language dominance in MEG. This study examines the concordance between MEG source localization of beta power desynchronization and fMRI with regard to lateralization and localization of expressive and receptive language areas using a visual verb generation task. Methods: Twenty-five patients with pharmaco-resistant epilepsy, including six patients with atypical language lateralization, and ten right-handed controls obtained MEG and fMRI language assessment. Fourteen patients additionally underwent the Wada test. We analyzed MEG beta power desynchronization in sensor (controls) and source space (patients and controls). Beta power decrease between 13 and 35 Hz was localized applying Dynamic Imaging of Coherent Sources Beamformer technique. Statistical inferences were grounded on cluster-based permutation testing for single subjects. Results: Event-related desynchronization of beta power in MEG was seen within the language-dominant frontal and temporal lobe and within the premotor cortex. Our analysis pipeline consistently yielded left language dominance with high laterality indices in controls. Language lateralization in MEG and Wada test agreed in all 14 patients for inferior frontal, temporal and parietal language areas (Cohen's Kappa = 1, p < 0.001). fMRI agreed with Wada test in 12 out of 14 cases (85.7%) for Broca's area (Cohen's Kappa = 0.71, p = 0.024), while the agreement for temporal and temporo-parietal language areas were non-significant. Concordance between MEG and fMRI laterality indices was highest within the inferior frontal gyrus, with an agreement in 19/24 cases (79.2%), and non-significant for Wernicke's area. Spatial agreement between fMRI and MEG varied considerably between subjects and brain regions with the lowest Euclidean distances within the inferior frontal region of interest. Conclusion: Localizing the desynchronization of MEG beta power using a verb generation task is a promising tool for the identification of language dominance in the pre-surgical evaluation of epilepsy patients. The overall agreement between MEG and fMRI was lower than expected and might be attributed to differences within the baseline condition. A larger sample size and an adjustment of the experimental designs are needed to draw further conclusions.

Barbiturates are a group of sedative-hypnotic medications used for the treatment of seizure disorder, neonatal withdrawal, insomnia, preoperative anxiety, induction of coma for increased intracranial pressure. They are also useful for inducing anesthesia. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring of the broad array of physiological possibilities when using barbiturates in the clinical setting.

Surgical treatment of pharmacoresistant temporal lobe epilepsy (TLE) carries risks for language function that can significantly affect the quality of life. Predicting the risks of decline in language functions before surgery is, consequently, just as important as predicting the chances of becoming seizure-free. The intracarotid amobarbital test, generally known as the Wada test (WT), has been traditionally used to determine language lateralization and to estimate their potential decline after surgery. However, the test is invasive and it does not localize the language functions. Therefore, other noninvasive methods have been proposed, of which functional magnetic resonance (fMRI) has the greatest potential. Functional MRI allows localization of language areas. It has good concordance with the WT for language lateralization, and it is of predictive value for postsurgical naming outcomes. Consequently, fMRI has progressively replaced WT for presurgical language evaluation. The objective of this manuscript is to review the most relevant aspects of language functions in TLE and the current role of fMRI and WT in the presurgical evaluation of language. First, we will provide context by revising the language network distribution and the effects of TLE on them. Then, we will assess the functional outcomes following various forms of TLE surgery and measures to reduce postoperative language decline. Finally, we will discuss the current indications for WT and fMRI and the potential usefulness of the resting-state fMRI technique.

Barbiturates are highly susceptible to dissociation in mass spectrometry (MS) because of their long side chains combined with a nonaromatic ring consisting of several carbonyl and amine groups. As a result, they exhibit extensive α-cleavage and subsequent rearrangement, making the identification of these compounds difficult. Although a library of electron ionization MS (EIMS) is available, most barbiturates have very similar fragment patterns. Accordingly, it would be desirable to develop a technique for soft ionization, providing a molecular ion and large fragment ions as well. In this study, a molecular ion was clearly observed, in addition to large fragment ions, for a variety of barbiturates based on multiphoton ionization MS (MPIMS) using a tunable ultraviolet femtosecond laser as the ionization source (fs-LIMS). This favorable result was achieved when the optimal laser wavelength for minimizing the excess energy remaining in the ionic state was used. An examination of the photofragmentation pathways suggested that an H atom in the side chain was abstracted by an oxygen atom in the carbonyl group in the ring structure thus initiating fragmentation and subsequent rearrangement. Barbiturates that are substituted with alkyl groups (amobarbital and pentobarbital) had narrower spectral regions for optimal ionization than the other barbiturates with alkyl and alkenyl groups (butalbital and secobarbital) and more with alkyl and phenyl groups (phenobarbital). All of the barbiturates studied provided unique mass spectral patterns in fs-LIMS, which was useful for the reliable identification of these compounds in practical trace analysis.

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF6 and [Ru(L)(dppe)2]PF6 where L = salicylic acid (Sal), 4-aminosalicylic acid (AmSal) or 2,4-dihydroxybenzoic acid (DiSal), dppb = 1,4-bis(diphenylphosphino)butane, dppe = 1,2-bis(diphenylphosphino)ethane and bipy = 2,2'-bipyridine. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR, UV-vis and IR spectroscopies, and two by X-ray crystallography. The 31P{1H} NMR spectra of the complexes with the general formula [Ru(L)(dppe)2]PF6 showed that the phosphorus signals are solvent-dependent. Aprotic solvents, which form strong hydrogen bonds with the complexes, inhibit the free rotation of the salicylic acid-based, modifying the diphosphine cone angles, leading to distortion of the phosphorus signals in the NMR spectra. The cytotoxicity of the complexes was evaluated in MCF-7, MDA-MB-231, SKBR3 human breast tumor cells, and MCF-10 non-tumor cell lines. The complexes with the structural formula [Ru(L)(dppe)2]PF6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe)2]PF6 with L = 4-aminosalicylic acid ligand was the most selective for the MDA-MB-231 cell line. This complex interacts with the transferrin and induces apoptosis through the intrinsic pathway, as demonstrated by increased levels of proteins involved in apoptotic cell death.

In high-stake cases (e.g., evaluating surgical candidacy for epilepsy) where neuropsychological evaluation is essential to care, it is important to have culturally and linguistically appropriate and accessible neuropsychological instruments and procedures for use with deaf individuals who use American Sign Language (ASL). Faced with these ethical and professional issues, clinicians may be unable to provide equitable services without consulting with other psychologists and collaborating with the patient and interpreter. This is a case report describing a 43-year-old male with bilateral sensorineural deafness and a lifelong history of drug-resistant temporal lobe epilepsy who presented as a candidate for a comprehensive neurological workup to determine surgical candidacy. He was bilingual (ASL and written English). We describe all aspects of the evaluation, including functional magnetic resonance imaging (fMRI) and Wada testing, using an ASL interpreter. Results from the neuropsychological evaluation were not clearly lateralizing, but suggested greater compromise to the non-dominant right hemisphere. fMRI and Wada test results revealed language and verbal memory functions were lateralized to the left hemisphere. The patient was deemed to be an adequate candidate for surgical resection of portions of the right hemisphere. Comprehensive assessment of neuropsychological functioning in deaf persons who use ASL is feasible. This case report illustrates the important considerations relevant to neuropsychologists providing culturally and linguistically informed assessments to deaf ASL users with epilepsy. Additional research in this area will support future efforts to develop effective and efficient models that could be implemented across different settings. Moreover, clinical guidance is warranted to guide professionals interested in promoting access to high quality neuropsychological services.

Barbiturates are a class of sedative-hypnotic drugs. They are commonly used as antiepileptics (phenobarbital) and for the induction of general anesthesia (thiopental). Some states administer barbiturates for physician-assisted suicide/euthanasia and use them for capital punishment by lethal injection. Their use in clinical practice has largely been replaced by benzodiazepines such as alprazolam, diazepam, and lorazepam due to the lower risk of overdose and available antidote to reverse toxicity. Barbiturates are used as a laboratory buffer and can be found in clinical and research laboratories.[1][2] Barbiturates are controlled substances that pose a high risk for abuse, given their psychoactive effects. Restrictions on access to barbiturates have caused the number of overdoses to decline. Common barbiturates include the following: Methohexital and thiopental are used as anesthetics. Phenobarbital and primidone are used in the treatment of seizures. Amobarbital is used as an investigative agent in the Wada test (neurological assessment of cerebral hemispheres)  Butalbital, in combination with other medications, is used for headaches and muscle pain.

Donation after circulatory death (DCD) donors are a potential source for heart transplantation. The DCD process has unavoidable ischemia and reperfusion (I/R) injury, primarily mediated through mitochondria, which limits routine utilization of hearts for transplantation. Amobarbital (AMO), a transient inhibitor of the electron transport chain, is known to decrease cardiac injury following ex vivo I/R. We studied whether AMO treatment during reperfusion can decrease injury in DCD hearts. Sprague Dawley rat hearts subjected to 25 minutes of in vivo ischemia (DCD hearts), or control beating donor hearts, were treated with AMO or vehicle for the first 5 minutes of reperfusion, followed by Krebs-Henseleit buffer reperfusion for 55 minutes (for mitochondrial isolation) or 85 minutes (for infarct size determination). Compared with vehicle, AMO treatment led to decreased infarct size (25.2% ± 1.5% vs. 31.5% ± 1.5%; P ≤ 0.05) and troponin I release (4.5 ± 0.05 ng/mL vs. 9.3 ± 0.24 ng/mL, P ≤ 0.05). AMO treatment decreased H 2 O 2 generation with glutamate as complex I substrate in both subsarcolemmal mitochondria (SSM) (37 ± 3.7 pmol·mg -1 ·min -1 vs. 56.9 ± 4.1 pmol·mg -1 ·min -1 ; P ≤ 0.05), and interfibrillar mitochondria (IFM) (31.8 ± 2.8 pmol·mg -1 ·min -1 vs. 46 ± 4.8 pmol·mg -1 ·min -1 ; P ≤ 0.05) and improved calcium retention capacity in SSM (360 ±17.2 nmol/mg vs. 277 ± 13 nmol/mg; P ≤ 0.05), and IFM (483 ± 20 nmol/mg vs. 377± 19 nmol/mg; P ≤ 0.05) compared with vehicle treatment. SSM and IFM retained more cytochrome c with AMO treatment compared with vehicle. In conclusion, brief inhibition of mitochondrial respiration during reperfusion using amobarbital is a promising approach to decrease injury in DCD hearts.

Activation of calpain1 (CPN1) contributes to mitochondrial dysfunction during cardiac ischemia (ISC) - reperfusion (REP). Blockade of electron transport using amobarbital (AMO) protects mitochondria during ISC-REP, indicating that the electron transport chain (ETC) is a key source of mitochondrial injury. We asked if AMO treatment can decrease CPN1 activation as a potential mechanism of mitochondrial protection during ISC-REP. Buffer-perfused adult rat hearts underwent 25 min global ISC and 30 min REP. AMO (2.5 mM) or vehicle was administered for 1 min before ISC to block electron flow in the ETC. Hearts in the time control group were untreated and buffer perfused without ISC. Hearts were collected at the end of perfusion and used for mitochondrial isolation. ISC-REP increased both the cleavage of spectrin (indicating cytosolic CPN1 activation) in cytosol and the truncation of AIF (apoptosis inducing factor, indicating mitochondrial CPN1 activation) in subsarcolemmal mitochondria compared to time control. Thus, ISC-REP activated both cytosolic and mitochondrial CPN1. AMO treatment prevented the cleavage of spectrin and AIF during ISC-REP, suggesting that the transient blockade of electron transport during ISC decreases CPN1 activation. AMO treatment decreased the activation of PARP [poly(ADP-ribose) polymerase] downstream of AIF that triggers caspase-independent apoptosis. AMO treatment also decreased the release of cytochrome c from mitochondria during ISC-REP that prevented caspase 3 activation. These results support that the damaged ETC activates CPN1 in cytosol and mitochondria during ISC-REP, likely via calcium overload and oxidative stress. Thus, AMO treatment to mitigate mitochondrial-driven cardiac injury can decrease both caspase-dependent and caspase-independent programmed cell death during ISC-REP.

We report a case study of a surgical candidate, a 51-year-old woman with left temporal lobe epilepsy, who failed a left injection intracarotid amobarbital procedure (e.g., Wada test), scoring 0 of 8 items. This raised concerns for postoperative memory decline. However, the patient was uninterested in a neuromodulatory approach and wished to be reconsidered for surgery. A stereotactic laser amygdalohippocampotomy (SLAH) was considered, encouraging the need for an alternative test to evaluate risk of memory decline. We developed a novel approach to testing memory during stimulation of a depth electrode implanted in the hippocampus, i.e., an electric Wada. During multiple stimulation trials across a range of amplitudes, the patient scored up to 8 of 8 items, which suggested strong contralateral memory support. The surgical team proceeded with a radiofrequency ablation and a subsequent SLAH. The patient remains seizure-free at 12 months post SLAH with no evidence of verbal or visuospatial memory decline based on a post-surgical neuropsychological battery. We believe that this case study provides a proof of concept for the feasibility and possible utility of an electric version of the Wada procedure. Future studies are needed to develop an optimal paradigm and to validate this approach.

A 31-year-old male with history of bipolar disorder, suicidal attempts requiring inpatient hospitalization, and seizures on antiepileptic medications presented with increasing seizure frequency. He was neurologically intact yet had multiple facial, axillary, and inguinal flat pigmented macules (cafe au lait spots) and ophthalmologic examination with iris hamartomas (Lisch nodules) consistent with neurofibromatosis type 1. Electroencephalogram was notable for multiple right temporal lobe seizures with anterior temporal interictal epileptiform discharges. Magnetic resonance imaging revealed a T2 hyperintense mass centered in the right amygdala, contiguous with the cystic area. Preoperative intracarotid sodium amobarbital testing showed left-sided language and memory dominance. The patient was operated on for right amygdalohippocampectomy, and initial pathology was consistent with a low-grade neuroepithelial neoplastic process. Further pathologic examination found hypercellular proliferation of predominantly bland, spindled cells with scattered, embedded neurocytic elements with dysplastic appearance, consistent with low-grade glioma. The patient was clinically diagnosed with neurofibromatosis type 1.

A mitochondrial electron transport chain member complex I inhibitor, amobarbital, can reduce oxidative damage and chondrocyte death, eventually preventing post-traumatic osteoarthritis (PTOA). Viscosupplementation using a crosslinked hyaluronic acid (HA) hydrogel is currently applied clinically for knee OA pain relief. In this work, we utilized the HA hydrogel as a drug delivery vehicle to improve the long-term efficacy of amobarbital. Here we evaluated the pharmaceutic stability of amobarbital when dispersed in a crosslinked HA hydrogel formulated in proportions intended for clinical use. We validated a high-performance liquid chromatography with an ultraviolet detector (HPLC-UV) method following International Conference for Harmonization Q2(R1) guidelines to ensure its suitability for amobarbital detection. The feasibility of this formulation's drug delivery capability was proven by measuring the release, solubility, and drug uniformity. The amobarbital/HA hydrogel showed comparable amobarbital stability in different biological fluids compared to amobarbital solution. In addition, the amobarbital/HA hydrogel imparted significantly greater drug stability when stored at 70°C for 24 hours. In conclusion, we confirmed the pharmaceutical stability of the amobarbital/HA hydrogel in various conditions and biological fluids using a validated HPLC-UV method. This data provides essential evidence in support of the use of this amobarbital/HA formulation in future clinical trials for PTOA treatment.

The intracarotid sodium amobarbital procedure (ISAP or Wada test) lateralizes cerebral functions to the cerebral hemispheres preoperatively. Functional magnetic resonance imaging (fMRI) is increasingly used to characterize preoperative language and memory lateralization. In this study, concordance of fMRI with Wada was examined in patients with medically intractable seizures. The relationship of the distance between the epileptogenic focus to functional activation area with patients' post-operative deficits in language was also analyzed. 27 epilepsy patients with preoperative fMRI and Wada data were analyzed using established fMRI paradigms for language and memory. Activation of Broca's and Wernicke's areas were measured in three dimensions. Language and memory lateralization were determined, and standard neuropsychiatry Wada test procedures were used for comparison. The shortest distance between a language area to the border of surgical focus (LAD) was also measured and compared with postoperative language deficits. Our study found that concordance between fMRI and Wada testing was 0.41 (Kappa's 'fair to good' concordance) for language dominance and 0.1 (Kappa's 'poor' concordance) for memory. No significant correlation was found between LAD and post-op language deficit (p=0.439). A correlation was found between LAD and post-op memory deficit (p=0.049; the further distance from surgical lesion to language area is associated with less post-operative memory loss). Females demonstrated significantly increased postoperative seizure improvement (Fisher's p-value=0.0296; female=8; male=6). A significant association between handedness (right-handed subjects) and postoperative seizure improvement was found (p=0.02) as well as a significant trend for interaction of gender and handedness on postoperative seizure improvement (p=0.09). Overall, our results demonstrate fMRI as a useful preoperative adjunct to Wada testing for language lateralization in patients with medically intractable seizures.

The Intracarotid amobarbital test (IAT), also called Wada test, is considered the "gold standard" for lateralizing language dominance in the pre-surgical evaluation of patients with epilepsy. In addition, it has been further modified to assess the postoperative risk of amnesia in patients undergoing temporal lobectomy. Since then it has been utilized to lateralize language and assess pre-surgical memory function. Over the years, its popularity has declined due to several limitations and availability of alternative procedures like fMRI and MEG. A survey of its use in the pre-surgical evaluation for epilepsy surgery has not been performed since the 2008 international survey by Baxendale et al. and it was heavily skewed due to data from European and North American countries. Only approximately 12% of the epilepsy centers indicated that they used the Wada test in every patient to assess preoperative memory function and language lateralization before temporal lobectomy. Nowadays, we have many functional mapping tools at our disposal. It has become somewhat unsuitable to have epilepsy patients undergo an invasive test such as the Wada test for the risks associated with it outweigh the benefits. Our objective is to review the Wada Test and alternative methods of assessing language and memory dominance, as it is past its prime and should only be used in specific circumstances.

Identification of the language dominant hemisphere is an essential part of the evaluation of potential pediatric epilepsy surgery patients. Historically, language dominance has been determined using the intracarotid amobarbitol procedure (IAP), but use of functional Magnetic Resonance Imaging (fMRI) scanning is becoming more common. Few studies examine the correspondence between fMRI and IAP in pediatric samples. The current study examined the agreement of hemispheric lateralization as determined by fMRI and IAP in a consecutive sample of 10 pediatric patients with epilepsy evaluated for epilepsy surgery. Data showed a strong correlation between IAP and fMRI lateralilty indices (r=.91) and 70% agreement in determination of hemispheric dominance, despite increased demonstration of bilateral or atypical language representation in this pediatric sample. Clinical implications and interpretation challenges are discussed.

Wada test is an invasive procedure used in the preoperative evaluation for epilepsy surgery to determine language lateralization, postoperative risk of amnesia syndrome, and to assess the risk of memory deficits. It involves injection of amobarbital into internal carotid artery of the affected hemisphere followed by the healthy hemisphere to shut down brain function. We performed an observational study evaluating the density spectral array (DSA) of the bilateral bispectral index VISTA™ Monitoring System (BVMS) in 6 patients with drug-resistant epilepsy undergoing Wada test. DSA revealed the presence of bifrontal alpha waves in absence of loss of consciousness in all patients.

Epilepsy surgery has progressed significantly in the last 150 years. Functional brain maps allowed for the localization of epileptogenic lesions based on seizure patterns, allowing surgeons like McEwan and Horsely to treat epilepsy surgically. Berger's electroencephalogram marked the first modality directly identifying epileptic abnormalities. Penfield and Jasper collaborated, as neurosurgeon and neurologist, to use EEG for surgery. Meanwhile, Wada developed the amobarbital test, improving the protection of language and memory. Talairach and Bancaud pioneered invasive monitoring of deep brain activity with stereoelectroencephalography before the computer age made CT and MRI possible. Looking forward, AI and robotics hold promise for further improving outcomes.

Due to supply shortage, amobarbital, the traditional anesthetic agent in Wada testing, was replaced by methohexital in many epilepsy centers. This study aimed to compare the two barbiturates to identify possible advantages or disadvantages of methohexital as compared to amobarbital with regard to the adequacy of language and memory testing during the Wada test.

Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure-Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (Mpro) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the Mpro of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the Mpro enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.

Damage to cerebral mitochondria, particularly opening of mitochondrial permeability transition pore (MPTP), is a key mechanism of ischemic brain injury, therefore, modulation of MPTP may be a potential target for a neuroprotective strategy in ischemic brain pathologies. The aim of this study was to investigate whether biguanides-metformin and phenformin as well as other inhibitors of Complex I of the mitochondrial electron transfer system may protect against ischemia-induced cell death in brain slice cultures by suppressing MPTP, and whether the effects of these inhibitors depend on the age of animals. Experiments were performed on brain slice cultures prepared from 5-7-day (premature) and 2-3-month old (adult) rat brains. In premature brain slice cultures, simulated ischemia (hypoxia plus deoxyglucose) induced necrosis whereas in adult rat brain slice cultures necrosis was induced by hypoxia alone and was suppressed by deoxyglucose. Phenformin prevented necrosis induced by simulated ischemia in premature and hypoxia-induced-in adult brain slices, whereas metformin was protective in adult brain slices cultures. In premature brain slices, necrosis was also prevented by Complex I inhibitors rotenone and amobarbital and by MPTP inhibitor cyclosporine A. The latter two inhibitors were protective in adult brain slices as well. Short-term exposure of cultured neurons to phenformin, metformin and rotenone prevented ionomycin-induced MPTP opening in intact cells. The data suggest that, depending on the age, phenformin and metformin may protect the brain against ischemic damage possibly by suppressing MPTP via inhibition of mitochondrial Complex I.