A case of epilepsia partialis continua of abdominal muscles after brain tumor surgery.

Epilepsia partialis continua (EPC) is a rare form of focal motor status epilepticus characterized by continuous muscular twitches or jerks involving a limited part of the body, usually facial region and distal limb. Although the cerebrovascular disease is known to be one of the most common causes of this condition, other reported cases with predominant abdominal involvement have different aetiologies, including, tumors, focal cortical dysplasia, and central nervous system infections. No cases of epilepsia partialis continua of the abdominal wall occurred after brain surgery have been previously reported. We describe the clinical, electrophysiological, and neuroimaging findings in an adult patient presenting with persistent unilateral abdominal myoclonus configuring an EPC as the evolution of a super-refractory hemibody convulsive status epilepticus, occurred after brain tumor surgery.

Subacute cerebellar ataxia as presenting symptom of systemic lupus erythematosus.

Neuropsychiatric manifestations are commonly observed in systemic lupus erythematosus (SLE) patients. In particular, neurological involvement is known to be more common in patients with positive anticardiolipin antibodies and lupus anticoagulants. Nevertheless, cerebellar ataxia has rarely been reported, especially as the first clinical manifestation of this systemic autoimmune disorder. Cerebral vascular infarction or ischemia, vasogenic oedema and antibody-mediated cerebral vasculopathy or vasculitic process have been supposed as possible aetiologies of acute cerebellar ataxia related to SLE. We report the clinical and radiological features of a woman who developed a rapidly progressive cerebellar syndrome as first sign of SLE; no other cause explaining her cerebellar ataxia was found. The patient improved after high-dose steroids. The appearance of a cerebellar syndrome with unknown aetiology with associated features of possible systemic autoimmune dysfunction, should be taken into account in clinical practice for appropriate diagnostic workup in order to provide effective therapeutic options.

Vagal Nerve Stimulation for Drug-Resistant Epilepsy: Adverse Events and Outcome in a Series of Patients with Long-Term Follow-Up.

BACKGROUND: Vagal nerve stimulation (VNS) is a palliative treatment option for drug-resistant epilepsy. The aim of this study was to describe the clinical and demographic features of selected patients scheduled for VNS and to evaluate the long-term efficacy of VNS in seizure control. MATERIALS AND METHODS: Between 2006 and 2013, 32 consecutive epileptic patients (14 male and 18 female) were enrolled at our Institute for VNS implantation. In all cases resective surgery had previously been excluded by the use of a noninvasive presurgical study protocol. Mean age was 32 years (range 18-50), and mean epilepsy duration 23 years (range 11-39). All subjects were followed-up for at least 2 years (mean 6 years, range 2-9) after VNS implantation. Patients were considered responders when a reduction of seizures of more than 50 % was reported. RESULTS: All patients had complex partial seizures, in 81 % of the patients with secondary generalization and in 56 % with drop attacks. Neurological examination revealed focal deficits in 19 % of the patients. Brain magnetic resonance imaging (MRI) was positive in 47 % of the patients. No surgical complications were observed in this series. Three patients were lost to follow-up. Twelve patients were classified as responders. Among the others, 1 patient experienced side effects (snoring and groaning during sleep) and the device was removed. CONCLUSIONS: Our data confirm that VNS is a safe procedure and a valid palliative treatment option for drug-resistant epileptic patients not suitable for resective surgery.

Stop-event-related potentials from intracranial electrodes reveal a key role of premotor and motor cortices in stopping ongoing movements.

In humans, the ability to withhold manual motor responses seems to rely on a right-lateralized frontal-basal ganglia-thalamic network, including the pre-supplementary motor area and the inferior frontal gyrus (IFG). These areas should drive subthalamic nuclei to implement movement inhibition via the hyperdirect pathway. The output of this network is expected to influence those cortical areas underlying limb movement preparation and initiation, i.e., premotor (PMA) and primary motor (M1) cortices. Electroencephalographic (EEG) studies have shown an enhancement of the N200/P300 complex in the event-related potentials (ERPs) when a planned reaching movement is successfully stopped after the presentation of an infrequent stop-signal. PMA and M1 have been suggested as possible neural sources of this ERP complex but, due to the limited spatial resolution of scalp EEG, it is not yet clear which cortical areas contribute to its generation. To elucidate the role of motor cortices, we recorded epicortical ERPs from the lateral surface of the fronto-temporal lobes of five pharmacoresistant epileptic patients performing a reaching version of the countermanding task while undergoing presurgical monitoring. We consistently found a stereotyped ERP complex on a single-trial level when a movement was successfully cancelled. These ERPs were selectively expressed in M1, PMA, and Brodmann's area (BA) 9 and their onsets preceded the end of the stop process, suggesting a causal involvement in this executive function. Such ERPs also occurred in unsuccessful-stop (US) trials, that is, when subjects moved despite the occurrence of a stop-signal, mostly when they had long reaction times (RTs). These findings support the hypothesis that motor cortices are the final target of the inhibitory command elaborated by the frontal-basal ganglia-thalamic network.

Changes in depression, anxiety, anger, and personality after resective surgery for drug-resistant temporal lobe epilepsy: a 2-year follow-up study.

OBJECTIVE: To further elucidate the psychiatric outcome of surgical treatment for temporal lobe epilepsy (TLE). METHODS: Fifty-two consecutive patients with drug-resistant TLE and IQ > or = 70 completed the Minnesota Multiphasic Personality Inventory, Beck Depression Inventory, Spielberger State-Trait Anxiety Inventory, and Spielberger State-Trait Anger Expression Inventory before epilepsy surgery, after 1 year, and after 2 years. Some patients also completed the 31-item Quality of Life in Epilepsy (N=29) and WHOQOL-100 (N=24) questionnaires. During the follow-up period, patients were maintained on a stable medication regimen. Multivariate repeated measures analysis of variance was used to examine changes in psychiatric variables over time. RESULTS: Seizure outcome was excellent (89% in Engel class I after 2 years). There were only a few significant changes over time in the MMPI profile, suggesting a decrease in interpersonal sensitivity, irritability, and social introversion. Anxiety decreased significantly with a gradual decline, anger dropped significantly after remaining basically flat during the first year, while depression showed a gradual but non-significant decline. Younger age and shorter duration of epilepsy were associated with greater improvement in several anger dimensions. In the patient subgroup with quality of life data available, greater improvement in overall quality of life and key life domains (income, work capacity, personal relationships) was found to be associated with greater decrease in depression, anxiety, and anger. CONCLUSION: The relatively slow decrease of emotional distress over time and its correlation with changes in some key life domains suggest that patients may experience difficulties in switching from a 'sick' role to a 'normal' role, and may easily be disappointed if expectations of positive life changes are not rapidly met. Some counselling sessions early after surgery may be useful to address these issues. The findings also suggest that surgery may yield greater emotional benefits if performed early.

Severe amnesia following bilateral medial temporal lobe damage occurring on two distinct occasions.

A comprehensive neuropsychological assessment was performed on a 38-year-old woman with drug-resistant right temporal lobe epilepsy before temporal lobectomy, during a 2-year follow-up period, and approximately 3 years after surgery when she developed a malignant glioma in the left medial temporal lobe (MTL). Both before and after epilepsy surgery, memory function was normal. When the tumour was discovered, the patient suffered from severe retrograde and anterograde amnesia, whereas working memory and the other cognitive abilities were preserved. Compared with other cases of bilateral temporal lesion, this case is peculiar because the damage occurred on two distinct occasions. It suggests that only one MTL can allow normal memory function, or can take over the function normally subserved by a dysfunctional contralateral MTL when the dysfunction is marked and prolonged, such as in chronic epilepsy.

Lateralizing value of memory tests in drug-resistant temporal lobe epilepsy.

Our aim was to test the lateralizing value of a neuropsychological battery including several memory tests on a large sample of consecutive patients with drug-resistant temporal lobe epilepsy (TLE) evaluated for epilepsy surgery. We studied 73 right-handed patients (56% males, mean age 35.3 +/- 11.2 years, 49% left TLE) aged 16 years or older with normal IQ who underwent a preoperative neuropsychological assessment including several memory tests and were seizure-free after at least 1 year of follow-up. Forty-seven had TLE due to hippocampal sclerosis, whilst 26 had TLE secondary to tumors or other lesions. Receiver Operating Characteristic (ROC) analysis and discriminant function analysis were used to evaluate the lateralization value of selected tests and of the battery as a whole, respectively. In patients with TLE secondary to tumors or other lesions, no test showed significant lateralizing value. In patients with TLE due to hippocampal sclerosis, the immediate (P < 0.01) and delayed (P < 0.001) Rey Auditory Verbal Learning Test (RAVLT) displayed substantial discriminatory ability. The battery as a whole correctly classified 82% of patients with respect to side of epileptogenesis. Our findings suggest that a non-invasive, relatively short and unexpensive neuropsychological battery based on memory tests may profitably complement other well-established diagnostic procedures such as video-EEG or magnetic resonance imaging (MRI), at least in patients with drug-resistant TLE due to hippocampal sclerosis.

A rapid and reliable procedure to localize subdural electrodes in presurgical evaluation of patients with drug-resistant focal epilepsy.

OBJECTIVES: To evaluate a novel method for localization of subdural electrodes in presurgical assessment of patients with drug-resistant focal epilepsy. METHODS: We studied eight consecutive patients with posterior epilepsy in whom subdural electrodes were implanted for presurgical evaluation. Electrodes were detected on post-implantation brain CT scans through a semiautomated procedure based on a MATLAB routine. Then, post-implantation CT scans were fused with pre-implantation MRI to localize the electrodes in relation to the underlying cortical structures. The reliability of this procedure was tested by comparing 3D-rendered MR images of the electrodes with electrode position as determined by intraoperative digital photography. RESULTS: In each patient, all electrodes could be correctly localized and visualized in a stereotactic space, thus allowing optimal surgery planning. The agreement between the procedure-generated images and the digital photographs was good according to two independent raters. The mean mismatch between the 3D images and the photographs was 2 mm. CONCLUSIONS: While our findings need confirmation on larger samples including patients with anterior epilepsy, this procedure allowed to localize subdural electrodes and to establish the spatial relationship of each electrode to the underlying brain structure, either normal or damaged, on brain convessity, basal and medial cortex. SIGNIFICANCE: Being simple, rapid, unexpensive, and reliable, this procedure holds promise to be useful to optimize epilepsy surgery planning.

Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy.

Pharmacotherapeutic strategies have been difficult to develop for several forms of temporal lobe epilepsy, which are consequently treated by surgical resection. To examine this problem, we have studied the properties of transmitter receptors of tissues removed during surgical treatment. We find that when cell membranes, isolated from the temporal neocortex of patients afflicted with drug-resistant mesial temporal lobe epilepsy (TLE), are injected into frog oocytes they acquire GABA type A receptors (GABA(A)-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABA(A)-receptor function is stable in oocytes injected with cell membranes isolated from the temporal lobe of TLE patients afflicted with neoplastic, dysgenetic, traumatic, or ischemic temporal lesions (lesional TLE, LTLE). Use-dependent GABA(A)-receptor rundown is also found in the pyramidal neurons of TLE neocortical slices and is antagonized by BDNF. Pyramidal neurons in cortical slices of a traumatic LTLE patient did not show GABA(A)-receptor rundown. However, the apparent affinity of GABA(A)-receptor in oocytes microtransplanted with membranes from all of the epileptic patients studied was smaller than the affinity of receptors transplanted from the nonepileptic brain. We conclude that the use-dependent rundown of neocortical GABA(A)-receptor represents a TLE-specific dysfunction, whereas the reduced affinity may be a general feature of brains of both TLE and LTLE patients, and we speculate that our findings may help to develop new treatments for TLE and LTLE.

Temporal lobe epilepsy surgery: different surgical strategies after a non-invasive diagnostic protocol.

AIM: To test a non-invasive presurgical protocol for temporal lobe epilepsy (TLE) based on "anatomo-electro-clinical correlations". METHODS: All consecutive patients with suspected TLE and seizure history <2 years were entered into the protocol, which included video-electroencephalographic (EEG) monitoring and magnetic resonance imaging (MRI). Three different TLE subsyndromes (mesial, lateral, mesiolateral) were identified by combined anatomical, electrical, and clinical criteria. "Tailored" surgery for each subsyndrome was offered. Patients with seizure history <2 years, MRI evidence of temporal mass lesion, and concordant interictal EEG and clinical data bypassed video-EEG monitoring and were directly scheduled for surgery. RESULTS: Lesionectomy was performed without video-EEG recording in 11 patients with tumorous TLE. Of 146 patients studied with video-EEG, 133 received a TLE diagnosis. Four were excluded for neuropsychological risks, eight refused surgery, and 121 underwent surgery. Of 132 consecutive patients who underwent surgery, 101 had at least one year of follow up. They were divided into a "hippocampal sclerosis/cryptogenic" group (n = 57) and a "tumours/cortical organisation disorders" group (n = 44). In the first group, extensive temporal lobectomy (ETL) was performed in 40 patients, anteromesial temporal lobectomy (AMTL) in 17 patients. At follow up, 47 patients were seizure free. In the second group, lesionectomy plus ETL was performed in 23 patients, lesionectomy plus AMTL in six patients, and lesionectomy alone in 15 patients. Thirty nine patients were seizure free. CONCLUSIONS: These findings suggest that different TLE subsyndromes can be identified accurately using non-invasive anatomo-electro-clinical data and can be treated effectively and safely with tailored surgery.

BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes.

Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABAA receptors, and we have shown previously that the "epileptic receptors" (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the "GABA currents" (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABAA receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant alpha1beta2gamma2 GABAA receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABAA currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC.

Cardiac asystole during right frontal lobe seizures: a case report.

The association between partial seizures and cardiac asystole has rarely been reported in the literature. This potentially life-threatening symptom has been observed principally in left-sided epilepsies, in particular during seizures originating in temporal lobe. We describe a case with ictal bradycardia followed by cardiac asystole during right frontal lobe seizures. Video-EEG monitoring recorded two partial seizures with electro-clinical findings suggestive of a right frontal lobe origin, associated with ictal bradycardia followed by prolonged asystole. The brain MRI showed a lesion located in the cingulate gyrus of the right frontal lobe. The patient required a subsequent placement of a pacemaker. In conclusion, cardiac asystole may be a potentially life-threatening symptom during seizures of frontal lobe origin. The right fronto-mesial structures may play a role in autonomic regulation of cardiovascular responses.

Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain.

The properties of gamma-aminobutyric acid (GABA) type A receptors (GABA(A) receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABA(A) receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat alpha 1 beta 2 gamma 2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABA(A) receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABA(A) receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABA(A)-receptor beta 1, beta 2, beta 3, and gamma 2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABA(A) receptors. Blockage of phosphatases stabilizes the TLE GABA(A) receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy.

Multiple spinal meningiomas after tamoxifen therapy: a case report.

We describe a rare case of multiple spinal meningiomas and evaluate the possible relationship with tamoxifen treatment. We observed a 74-year-old woman who showed a spastic paraparesis gradually developed in the last year. The patient underwent left mastectomy for a breast cancer ten years earlier and was treated with tamoxifen for four years after surgical intervention. Magnetic resonance imaging revealed three spinal meningiomas at C6-C7, D6-D7 and D9 levels. Taking in account the tumor-inducing properties of tamoxifen and the extreme rarity of multiple spinal meningiomas, we suggest that tamoxifen may be the cause play a role in the genesis of the spinal meningiomatosis in the observed patient. Therefore, we propose the long-term clinical and neurological surveillance of patients who assumed tamoxifen, even for a short time, in order to survey the possible appearance of secondary tumours.

Picotamide, an antithromboxane agent, inhibits the migration and proliferation of arterial myocytes.

Picotamide is an antiplatelet drug with a peculiar dual mechanism of action: it inhibits thromboxane A2 synthase and antagonizes the pharmacological responses mediated by thromboxane A2 receptor. We investigated the in vitro effect of picotamide on smooth muscle cell migration and proliferation. Picotamide (1-500 microM) decreased human and rat smooth muscle cell proliferation, evaluated as cell number, in a concentration-dependent and reversible manner. Picotamide inhibited DNA synthesis induced by fetal calf serum (10%), platelet-derived growth factor (PDGF-BB (20 ng/ml)), epidermal growth factor (EGF (1 nM)) and (15S)-hydroxy-11,9-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619 (10 microM, thromboxane A2 receptor agonist)). Co-incubation of U46619 together with EGF or PDGF-BB resulted in a marked amplification of [3H]thymidine incorporation that was completely reversed by picotamide. The drug also inhibited smooth muscle cell migration induced by fibrinogen (600 microg/ml) or PDGF-BB (20 ng/ml) in a concentration-dependent manner. The ability of picotamide to interfere with myocyte migration and proliferation confers, at least in vitro, a pharmacological interest on the compound in atherogenesis.

Direct vascular effects of HMG-CoA reductase inhibitors.

Several studies have demonstrated that any beneficial effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events are linked to their hypocholesterolemic properties. However, since mevalonic acid (MVA), the product of the enzyme reaction, is the precursor of numerous metabolites, inhibition of HMG-CoA reductase has the potential to result in pleiotropic effects. MVA and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, hence effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently, we provided in vitro evidence that fluvastatin, simvastatin, lovastatin, cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cells (SMC) migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages, by blocking cholesterol esterification and endocytosis of modified lipoproteins. This in vitro inhibition was completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through a prenylated protein(s)--in regulating these cellular events. The inhibitory effect of lipophilic statins on SMC proliferation has been recently shown in different models of proliferating cells such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently showed that sera from fluvastatin-treated patients interfere with smooth muscle cell proliferation. These results suggest that HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect in the arterial wall, beyond their effects on plasma lipids, that could translate into a more significant prevention of cardiovascular disease.

Pharmacological control of the mevalonate pathway: effect on arterial smooth muscle cell proliferation.

The mevalonate (MVA) pathway is involved in cell proliferation. We investigated drugs acting at different enzymatic steps on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (0.1-10 microM) dose-dependently decreased (up to 90%) SMC proliferation. This effect was prevented by 100 microM MVA, 10 microM all-trans farnesol (F-OH) and 5 microM all-trans geranylgeraniol (GG-OH), precursors of protein prenyl groups, but not by 2-cis GG-OH, precursor of dolichols, squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-pyrophosphate decarboxylase. Partial recovery of cell proliferation was possible by all-trans F-OH and all-trans GG-OH, but not MVA. Squalestatin 1 (1-25 microM), a potent squalene synthase inhibitor, blocked cholesterol synthesis and slightly inhibited (21% decrease) SMC proliferation only at the highest tested concentration. NB-598 (1-10 microM), a potent squalene epoxidase inhibitor, blocked cholesterol synthesis without affecting SMC proliferation. Finally, the benzodiazepine peptidomimetic BZA-5B (10-100 microM), a specific inhibitor of protein farnesyltransferase, time- and dose-dependently decreased SMC proliferation (up to 62%) after 9 days. This effect of BZA-5B was prevented by MVA and all-trans GG-OH, but not by all-trans F-OH. SMC proliferation was not affected by the closely related compound BZA-7B, which does not inhibit protein farnesyltransferase. Altogether, these findings focus the role of the MVA pathway in cell proliferation and call attention to the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins, in the control of this cellular event.

[Pharmacological control of biosynthesis pathway of mevalonate: effect on the proliferation of arterial smooth muscle cells]. / Contrôle pharmacologique de la voie de biosynthèse du mévalonate: effet sur la prolifération de cellules musculaires lisses artérielles.

The role of mevalonic acid (MVA) and its products (isoprenoids) in cell proliferation prompted us to investigate the effect of drugs affecting diverse enzymatic steps of the MVA pathway on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of HMG-CoA reductase (statins) decreased SMC proliferation in a dose-dependent manner. The inhibitory effect induced by simvastatin 3.5 microM (70% +/- 3.8 decrease) was prevented by addition of 100 microM MVA, (100% +/- 2.3), 10 microM farnesol (F-OH) (85% +/- 1.2) and 5 microM of all-trans geranylgeraniol (GG-OH) (precursor of prenylated proteins) (81% +/- 1.1), but not by 2-cis GG-OH (precursor of dolichols), squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-PP decarboxylase. Squalestatin 1 (1-25 microM) and NB-598 (1-10 microM), potent squalene synthase and epoxidase inhibitors, respectively, caused a complete inhibition of cholesterol synthesis without affecting SMC proliferation. Finally, BZA-5B (10-50 microM) a specific inhibitor of protein farnesyl tranferase (PFTase), inhibited SMC proliferation in a dose- (10-50 microM) and time-dependent manner, reaching 52% +/- 6.3 inhibition after 9 days, in the presence of 50 microM BZA-5B, without affecting cholesterol synthesis. This effect was partially prevented by mevalonate (76% +/- 3.2) and GG-OH (87% +/- 7.3) but not by F-OH. On the other hand, SMC proliferation was not affected by the closely related compound BZA-7B (93% +/- 4), which does not inhibit PFTase. Taken together, these findings support the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins in cell proliferation.