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Objective: In this pilot prospective cohort study, we aimed to evaluate, using high-density electroencephalography (HD-EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA)., Background: OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited., Methods: This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD-EEG was recorded using a 64-channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ-θ-α-β-low-γ bands was analyzed using the weighted phase-lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross-validation methods to estimate the results' reliability., Results: Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76-0.98], Cohen's κ [0.65-0.93]) and β (p = 0.031, AUC [0.68-0.95], Cohen's κ [0.51-0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80-0.99], Cohen's κ [0.42-0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73-0.99], Cohen's κ [0.53-0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58-0.93], Cohen's κ [0.37-0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex., Conclusion: These preliminary results showed that patients with CM presented disrupted EEG-FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background and Purpose: Idiopathic normal pressure hydrocephalus (iNPH) pathogenesis is multifactorial. Systemic inflammation might have a role in gathering clinical-pathological trajectories. We aimed to shape the peripheral immune profile of iNPH and establish correlations with cerebrospinal fluid (CSF) markers, ventricular enlargement, and clinical outcomes., Methods: We conducted a single-center retrospective-longitudinal study, including 38 iNPH patients and 38 controls. Baseline iNPH Grading Scale and modified Rankin Scale (mRS) scores were collected with peripheral blood cell count, CSF amyloid-β42 (Aβ42), total tau (t-tau), phosphorylated-181-tau, and Evans index. Depending on 5-year outcome, iNPH patients were grouped into "poor outcome" (PO; mRS ≥ 5) and "favorable outcome" (FO; mRS < 5). Biomarkers were compared and correlated with each other. Receiver operating characteristic analysis was performed., Results: iNPH patients compared to controls had higher neutrophil-to-lymphocyte ratio (NLR; 2.43 ± 1.04 vs. 1.61 ± 0.47, p < 0.001), higher neutrophils (4.22 ± 0.86 1000/mL vs. 3.48 ± 1.34, p = 0.033), and lower lymphocytes (1.45 ± 0.55 1000/mL vs. 2.07 ± 0.86, p = 0.038), with the expected CSF biomarkers signature. In the patients' cohort, NLR was associated directly with t-tau and inversely with Aβ42. NLR directly correlated with Evans index. PO patients compared to those with FO had higher NLR (3.25 ± 1.40 vs. 2.01 ± 0.77, p = 0.035) and higher t-tau (274.76 ± 114.39 pg/mL vs. 150.28 ± 72.62, p = 0.017), with an area under the curve of 0.786 and 0.793, respectively., Conclusions: iNPH patients present a proinflammatory state associated with neurodegeneration and predicting poor clinical outcome. Systemic inflammation represents a factor in the clinical-pathological progression of iNPH, and the NLR emerges as a potential prognostic index., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Inflammation is an important player in Alzheimer's disease (AD), whose effects can be influenced by the blood-brain barrier (BBB). Here, we investigated the relationship between BBB permeability, indicated by cerebrospinal fluid (CSF)/plasma albumin quotient (Qalb), and CSF indexes of neuroinflammation in a cohort of biologically defined AD patients., Methods: Fifty-nine consecutive patients with mild cognitive impairment (MCI) or early AD (Mini-Mental State Examination [MMSE] >22) underwent CSF analysis for inflammatory cytokines (interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, Il-10, IL-12, IL-13, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], granulocyte-monocyte colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF]). Using backward stepwise linear regression analysis, we explored the potential influence of each cytokine CSF level on Qalb considering age, sex, and apolipoprotein E (APOE) as covariates., Results: Higher levels of IL-4 (β = 0.356, 0.005) and IL-8 (β = 0.249, 0.05) were associated with higher Qalb values, while macrophage inflammatory protein-1α (MIP-1β) (β = -0.274; p = 0.032) and TNF-α (β = -0.248; p = 0.031) showed a significant negative association with BBB permeability. Age was also positively associated with Qalb (β = 0.283; p = 0.016)., Conclusions: Despite the overall integrity of the BBB, its permeability could either influence or be influenced by central neuroinflammation, reflected by CSF cytokine levels. This is in line with previous studies that showed that patients with a more intact barrier are those with more prominent neurodegeneration. Our findings suggest that different neuroinflammatory profiles can be associated with different levels of BBB permeability in AD., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical-pathological features in male PD patients., Methods: A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloid-β-42, amyloid-β-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses., Results: Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α-synuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloid-β-42/amyloid-β-40 ratio., Conclusions: The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline., (© 2023 European Academy of Neurology.)

Background and Purpose: The locus coeruleus (LC) provides dopamine/noradrenaline (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes., Methods: The CSF concentration of DA transporter (DAT), tyrosine-hydroxylase (TH), DOPA-decarboxylase (DDC), and dopamine-β-hydroxylase (DβH), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta-amyloid (Aβ) 1-42 (A) and p-tau (T) in AD pathological changes (A+ T-) and AD (A+ T+) subgroups, as well as in 15 control subjects (A- T-)., Results: The ADc group had lower CSF levels of DAT and TH but increased DβH levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but comparable with controls in the A+ T- subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and Aβ 1-42 (R 2  = 0.25) and between DDC and p-tau (R 2  = 0.33). Finally, TH correlated with interleukin (IL)-10 levels (p = 0.0008) and DβH with IL-1β (p = 0.03), IL-4 (p = 0.02), granulocyte colony-stimulating factor (p = 0.007), and IL-17 (p = 0.01)., Conclusions: Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurodegenerative and neuroinflammatory processes in AD pathology., (© 2023 European Academy of Neurology.)

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterizing patients with LGS. Highly purified cannabidiol (CBD) is a novel antiseizure medication (ASM) recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous ASM treatment helps in reducing seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait, and stability are available. In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected. Our case series suggests that CBD may help in managing patients with LGS regarding seizure control and in improving other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug's effect on the brain locomotor centers, as demonstrated in animal model studies., (© 2023 International League Against Epilepsy.)

Background and Purpose: Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ 1-42 ) and phosphorylated tau (T: p-tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T-) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process., Methods: For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping., Results: A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T- patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t-tau) levels compared to non-DM patients (DM: 919.4 ± 444 vs. non-DM: 773.1 ± 348.2; p = 0.04), but similar p-tau (p = 0.72) and Aβ 1-42  levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t-tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49-398.1; p = 0.01), but not in APOE E4- (p = 0.53)., Conclusions: The present study shows a clear dependency of CSF t-tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4-related and non-related disease, with key implications for AD pathophysiology and treatment., (© 2021 European Academy of Neurology.)

Background: COVID-19 outbreak profoundly affected health systems and people's daily life worldwide. Parkinson's disease (PD) patients lost their normal routine and interrupted regular physical activity, either as physiotherapy or sport, with inevitable consequence on their daily-life and well-being., Objectives: To evaluate the changes in physical activity due to COVID-19 emergency, including self-management strategies or technology-assisted activities, and the subsequent clinical implications in PD patients., Methods: Seventy-four patients from an Italian center have been remotely examined during the lockdown (April-May 2020) by an e-mail structured survey, including self-administered scales. We collected and analyzed data on changes, modalities and amount of physical active practice, on the use of technology-based tools, and on self-perceived clinical condition., Results: Sixty percent of patients reported a significant worsening of their general conditions during the lockdown, the reduction of physical activity being the main risk factor for such change. However, patients found ways to practice physical activity, using satisfactorily technology assistance in 50% of cases (mostly women)., Conclusions: The COVID-19 emergency has been an ordeal for PD patients. Nevertheless, patients adapted their habits to continue practicing physical activity that resulted a main determinant of their well-being; as well, they successfully approached technology-based assistance. Education, communication, and networking emerge as critical for a constructive reaction to the emergency's challenges., (© 2020 International Parkinson and Movement Disorder Society.)

Perampanel (PER) and brivaracetam (BRV) are third-generation antiseizure medications. The aim of the present retrospective, double-centre study was to compare the effectiveness and tolerability between PER and BRV in adult patients with epilepsy. We reviewed the clinical charts of patients affected by epilepsy, admitted to the Epilepsy Centre at the University Hospital of Rome "Tor Vergata" and the Cardarelli Hospital in Naples, who started BRV or PER as add-on treatment for controlling seizures with a follow-up of 12 months. Seizure freedom, >50% seizure reduction, retention rate, and adverse events reported during follow-up were compared between the two drugs. Moreover, we considered the effects of both drugs in specific subsets of patients: age ≥60 years, male or female, in patients with genetic generalized epilepsy, and considering previous treatment with levetiracetam (LEV). Forty-three patients treated with BRV and 64 patients treated with PER were included in this study and followed at both sites for 12 months. Similar effectiveness was observed between BRV and PER, with similar rates of seizure freedom (30% vs 31%) and >50% seizure reduction (32% vs 34%) during follow-up. Moreover, PER and BRV discontinuation rates, due to ineffectiveness or adverse events, were similar. Groups of patients who started BRV or PER as first add-on treatments were also compared but no differences in effectiveness or tolerability were identified. Lastly, BRV was shown to be more effective in patients who were not previously treated with LEV. This retrospective study reveals comparable effectiveness and tolerability between PER and BRV also when used as first add-on treatments, in patients with epilepsy.

Background and Purpose: One of the hallmarks of ventral midbrain dopamine-releasing neurons is membrane hyperpolarization in response to stimulation of somato-dendritic D 2 receptors. At early postnatal age, under sustained dopamine, this inhibitory response is followed by a slow recovery, resulting in dopamine inhibition reversal (DIR). In the present investigation, we aimed to get a better insight into the cellular mechanisms underlying DIR., Experimental Approach: We performed single-unit extracellular recordings with a multi-electrode array device and conventional patch-clamp recordings on midbrain mouse slices., Key Results: While continuous dopamine (100 μM) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D 2 receptor agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABA B receptor agonist baclofen (300 nM) was reversed by dopamine (100 μM), albeit D 2 receptors had been blocked by sulpiride (10 μM). Conversely, the block of the dopamine transporter (DAT) with cocaine (30 μM) prevented firing recovery by dopamine under GABA B receptor stimulation. Accordingly, in whole-cell recordings from single cells, the baclofen-induced outward current was counteracted by dopamine (100 μM) in the presence of sulpiride (10 μM), and this effect was prevented by the DAT antagonists cocaine (30 μM) and GBR12909 (2 μM)., Conclusions and Implications: Our results indicate that the DAT plays a major role in DIR, mediating it under conditions of sustained dopamine exposure, and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the dopaminergic signal., (© 2018 The British Pharmacological Society.)

Background and Purpose: The aim was to investigate the prevalence of restless legs syndrome (RLS), fatigue and daytime sleepiness in a large cohort of patients affected by post polio syndrome (PPS) and their impact on patient health-related quality of life (HRQoL) compared with healthy subjects., Methods: PPS patients were evaluated by means of the Stanford Sleepiness Scale and the Fatigue Severity Scale (FSS). The Short Form Health Survey (SF-36) questionnaire was utilized to assess HRQoL in PPS. RLS was diagnosed when standard criteria were met. Age and sex matched healthy controls were recruited amongst spouses or friends of PPS subjects., Results: A total of 66 PPS patients and 80 healthy controls were enrolled in the study. A significantly higher prevalence of RLS (P < 0.0005; odds ratio 21.5; 95% confidence interval 8.17-57) was found in PPS patients (PPS/RLS+ 63.6%) than in healthy controls (7.5%). The FSS score was higher in PPS/RLS+ than in PPS/RLS- patients (P = 0.03). A significant decrease of SF-36 scores, including the physical function (P = 0.001), physical role (P = 0.0001) and bodily pain (P = 0.03) domains, was found in PPS/RLS+ versus PPS/RLS- patients. Finally, it was found that PPS/RLS+ showed a significant correlation between International Restless Legs Scale score and FSS (P < 0.0001), as well as between International Restless Legs Scale score and most of the SF-36 items (physical role P = 0.0018, general health P = 0.0009, vitality P = 0.0022, social functioning P = 0.002, role emotional P = 0.0019, and mental health P = 0.0003)., Conclusion: Our findings demonstrate a high prevalence of RLS in PPS, and that RLS occurrence may significantly influence the HRQoL and fatigue of PPS patients. A hypothetical link between neuroanatomical and inflammatory mechanisms in RLS and PPS is suggested., (© 2014 EAN.)

Background and Purpose: There is a paucity of data available regarding the occurrence of sleep disorders in myotonic dystrophy type 2 (DM2). In this study the sleep-wake cycle and daytime sleepiness were investigated in DM2 patients and compared with results from healthy subjects and myotonic dystrophy type 1 (DM1) patients., Methods: Twelve DM2 outpatients, 12 age- and sex-matched healthy controls and 18 DM1 patients were recruited. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). Both the Epworth Sleepiness Scale and the Daytime Sleepiness Scale were performed in order to evaluate excessive daytime sleepiness (EDS). All participants underwent polysomnographic monitoring over 48 h as well as the Multiple Sleep Latency Test., Results: Sleep efficiency was < 90% in 12/12 DM2 patients, and significantly reduced when compared with controls or with DM1. Decreased sleep efficiency was associated with sleep-disordered breathing in seven out of 12 DM2 patients and/or periodic limbs movements of sleep (PLMS) in three out of eight patients. Six DM2 patients showed REM sleep without atonia, whereas none of the controls or DM1 patients showed REM sleep dysregulation. The global PSQI score was higher in DM2 patients than in controls and DM1 patients., Conclusions: Sleep quality in DM2 patients is poorer than in DM1 patients and controls. Sleep apnea is the most common sleep disorder in DM2 patients. Obstructive sleep apnea and sleep fragmentation may represent the main cause of EDS, whereas PLMS is a frequent finding in DM1., (© 2013 The Author(s) European Journal of Neurology © 2013 EAN.)

For many years after its discovery, hydrogen peroxide (H₂O₂) was viewed as a toxic molecule to human tissues; however, in light of recent findings, it is being recognized as an ubiquitous endogenous molecule of life as its biological role has been better elucidated. Indeed, increasing evidence suggests that H₂O₂ may act as a second messenger with a pro-survival role in several physiological processes. In addition, our group has recently demonstrated neuroprotective effects of H₂O₂ on in vitro and in vivo ischaemic models through a catalase (CAT) enzyme-mediated mechanism. Therefore, the present review summarizes experimental data supporting a neuroprotective potential of H₂O₂ in ischaemic stroke that has been principally achieved by means of pharmacological and genetic strategies that modify either the activity or the expression of the superoxide dismutase (SOD), glutathione peroxidase (GPx) and CAT enzymes, which are key regulators of H₂O₂ metabolism. It also critically discusses a translational impact concerning the role played by H₂O₂ in ischaemic stroke. Based on these data, we hope that further research will be done in order to better understand the mechanisms underlying H₂O₂ functions and to promote successful H₂O₂ signalling based therapy in ischaemic stroke., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background and Purpose: Although trace amines (TAs) are historically considered 'false neurotransmitters' on the basis of their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors, ligand-gated receptor channels and/or sigma receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and beta-phenylethylamine (beta-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to the D(2) receptor agonist, quinpirole., Experimental Approach: Electrophysiological recordings of D(2) receptor-activated G-protein-gated inward rectifier K(+) channel (GIRK) currents were performed on dopaminergic cells from midbrain slices of mice and on Xenopus oocytes expressing D(2) receptors and GIRK channels., Key Results: TYR and beta-PEA reversibly reduced D(2) receptor-activated GIRK currents in a concentration-dependent manner on SNpc neurones. The inhibitory effect of TAs was still present in transgenic mice with genetically deleted TA(1) receptors and they could not be reproduced by the selective TA(1) agonist, o-phenyl-3-iodotyramine (O-PIT). Pretreatment with antagonists of sigma1 and sigma2 receptors did not block TA-induced effects. In GTPgammaS-loaded neurones, the irreversibly-activated GIRK-current was still reversibly reduced by beta-PEA. Moreover, beta-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes., Conclusions and Implications: TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from TA(1), sigma-receptors, D(2) receptors or GIRK channels. Although their precise mechanism of action remains to be identified, TAs, by antagonizing the inhibitory effects of dopamine, may render dopaminergic neurones less sensitive to autoreceptor feedback inhibition and hence enhance their sensitivity to stimulation.

Background and Purpose: Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells., Experimental Approach: Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABA(A) and GABA(B) receptors., Key Results: Fenfluramine and sibutramine reduced, concentration-dependently, the GABA(B) IPSPs, without affecting the GABA(A)-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABA(B) receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT(1B)) receptor antagonist, SB216641, blocked the reduction of GABA(B) IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT(1B)., Conclusions and Implications: Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT(1B) receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour.

Background and Purpose: Reactive oxygen species (ROS) have been postulated to play a crucial role in the pathogenesis of ischaemia-reperfusion injury. Among these, hydrogen peroxide (H(2)O(2)) is known to be a toxic compound responsible for free-radical-dependent neuronal damage. In recent years, however, the 'bad reputation' of H(2)O(2) and other ROS molecules has changed. The aim of this study was to assess the protective role of H(2)O(2) and modification in its endogenous production on the electrophysiological and morphological changes induced by oxygen/glucose deprivation (OGD) on CA1 hippocampal neurons., Experimental Approach: Neuroprotective effects of exogenous and endogenous H(2)O(2) were determined using extracellular electrophysiological recordings of field excitatory post synaptic potentials (fEPSPs) and morphological studies in a hippocampal slice preparation. In vitro OGD was delivered by switching to an artificial cerebrospinal fluid solution with no glucose and with oxygen replaced by nitrogen., Key Results: Neuroprotection against in vitro OGD was observed in slices treated with H(2)O(2) (3 mM). The rescuing action of H(2)O(2) was mediated by catalase as pre-treatment with the catalase inhibitor 3-amino-1,2,4-triazole blocked this effect. More interestingly, we showed that an increase of the endogenous levels of H(2)O(2), due to a combination of an inhibitor of the glutathione peroxidase enzyme and addition of Cu,Zn-superoxide dismutase in the tissue bath, prevented the OGD-induced irreversible depression of fEPSPs., Conclusions and Implications: Taken together, our results suggest new possible strategies to lessen the damage produced by a transient brain ischaemia by increasing the endogenous tissue level of H(2)O(2).

1. The effects of donepezil, one of the most common cholinesterase inhibitors used for treatment of Alzheimer's disease, were studied on nicotinic receptors (nAChRs)-mediated postsynaptic currents, in dopaminergic neurons of the substantia nigra pars compacta, using the patch-clamp recording technique in slice preparations. 2. Donepezil (10-100 microM) selectively and reversibly depressed nicotine currents, induced by brief puffer pulses, through a glass micropipette positioned above the slice. 3. The peak amplitude fading of the responses generated by repeated test applications of low doses of nicotine was accelerated by donepezil, while it slowed the recovery of nicotine currents after a large, desensitising, dose of the same agonist. 4. Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent. 5. Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine-induced currents. The data indicated direct effect on nAChR, independent from the activity of donepezil as cholinesterase inhibitor.

1. The electrophysiological effects of riluzole on rat prefrontal and frontal cortical neurones were investigated by using both extracellular (field) and intracellular recording techniques in brain slices. 2. Bath applied riluzole (3-200 microM) depressed the cortico-cortical stimulus-evoked field potential in a concentration-related manner (EC50 = 29.5 microM). 3. Riluzole (3-100 microM) reduced the tonic firing of the neocortical neurones which was caused by intracellular current injection, while it did not have any effect on the resting membrane potential and apparent input resistance of these cells. 4. In the presence of tetrodotoxin (1 microM) and tetraethylammonium (30 mM), the injection of a depolarizing current step generated a calcium spike in the neocortical neurones. Riluzole (30 microM) abolished this calcium-dependent action potential. However, when the amount of the depolarizing current was increased the calcium-dependent regenerative potential was evoked again. 5. The depolarization of the membrane (10-20 mV) caused by brief (8-15 s) bath applications of glutamate (300 microM-1 mM) were not changed in the presence of riluzole (30 microM). 6. It is concluded that riluzole has direct actions on rat neocortical neurones: (a) it blocks the repetitive discharge of sodium action potentials and (b) it increases the threshold for the generation of the calcium spike. These two cellular mechanisms might at least in part account for the depression of the cortico-cortical field potential caused by this drug.

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

1. We have investigated the effects of the anticonvulsant drug, felbamate (FBM), on striatal neurones, recorded in vitro by using both intracellular and extracellular conventional recordings in slices and whole-cell recordings in acutely isolated neurones. 2. FBM, at therapeutically relevant concentrations (30-300 microM) showed multiple mechanisms of action. Like other antiepileptic drugs, FBM (30-300 microM) showed a direct inhibitory action on current-evoked firing discharge of striatal neurones. A patch-clamp analysis of this effect revealed a dose-related reduction of voltage-dependent sodium (Na+) currents (10-100 microM), with a half inhibiton dose (IC50) value of 28 microM. 3. We also tested whether FBM affected corticostriatal glutamate transmission. In control medium (1.2 mM external magnesium), both extracellularly recorded field potentials and intracellularly recorded excitatory postsynaptic potentials (e.p.s.ps) evoked by cortical stimulation were no affected by bath application of 30-300 microM FBM. 4. When magnesium was removed from the perfusing solution, a procedure which reveals a N-methyl-D-aspartate (NMDA)-mediated component in the corticostriatal synaptic potential, FBM (30-300 microM) produced a dose-dependent reduction of the amplitude of both the field potential and the e.p.s.p. 5. FBM reduced the inward currents produced either by bath or by focal applications of 30 microM NMDA, finding consistent with the hypothesis that the observed reduction of the NMDA-mediated component of the synaptic potentials may be caused at postsynaptic level. 6. The reduction of the NMDA-mediated component of the synaptic transmission by FBM and its depressant effect on the voltage-dependent Na+ channels, may account for the antiepileptic action of this drug. Moreover, the pharmacological properties of FBM might render this drug interesting as a neuroprotectant agent.

1. The effects of the dihydropyridine calcium channel antagonists, nifedepine and nimodipine (300 nM-30 microM) were tested in vitro on intracellularly recorded dopaminergic neurones in the rat ventral mesencephalon. 2. Bath applied nifedipine and nimodipine inhibited in a concentration-dependent manner the spontaneous firing discharge of the action potentials, whereas, the dihydropyridine calcium channel agonist, Bay K 8644 increased the firing rate. 3. Pacemaker oscillations and bursts of action potentials were produced by loading the cells with caesium. Nifedipine and nimodipine reduced the rate and the duration of the caesium-induced membrane oscillations and decreased the number of action potentials in a burst. During the blockade of potassium currents the dopaminergic neurones often developed a prolonged (100-800 ms) afterdepolarization that was also inhibited by dihydropyridines. 4. The spontaneous discharge of calcium spikes was also inhibited by both dihydropyridine calcium antagonists. The apparent input resistance and the level of membrane potential were not affected by the dihydropyridine calcium antagonists. 5. If the action potential duration was less than 150 ms the shape of the spike was not clearly influenced by both calcium antagonists. However, when the duration of the action potential was longer than 150-200 ms due to the intracellular injection of caesium ions plus the extracellular application of tetraethylammonium (10-50 mM), both nifedipine and nimodipine reversibly shortened the plateau potential. 6. It is suggested that nifedipine and nimodipine depress the rhythmic and bursting activity of the dopaminergic cells and shorten the calcium action potential by blocking dihydropyridine-sensitive high-threshold calcium currents.

1. Intracellular recordings were made from substantia nigra pars compacta neurones of the rat maintained in vitro in order to study the effects of the tricyclic antidepressant drug, amineptine. 2. Amineptine hydrochloride (1-30 microM) decreased spontaneous firing and slightly hyperpolarized the membrane potential. In neurones voltage-clamped at -50 or -60 mV, amineptine produced an outward membrane current. These actions were concentration-dependent and were completely antagonized by (-)-sulpiride. 3. The amineptine-induced hyperpolarization was resistant to tetrodotoxin (1 microM) but it was abolished in 0 mM Ca2+ (plus 13 mM MgCl2) solutions. 4. Amineptine (300 nM-30 microM) and cocaine (10-30 microM) increased the amplitude and duration of responses to exogenously applied dopamine. The effects of dopamine were potentiated about 5 fold by 10 microM amineptine; this potentiation persisted in calcium-free solutions. 5. Cocaine (10 microM) had no additional effect on the dopamine-induced responses in the presence of amineptine (30 microM). Amineptine (10 microM) produced no detectable effects in the presence of cocaine (30 microM). 6. It is concluded that amineptine acts as a dopamine uptake blocker in slices of rat substantia nigra.

1. The electrophysiological actions of L-DOPA were studied on substantia nigra dopamine-containing neurones by use of intracellular recordings, current and voltage clamp, in vitro. 2. L-DOPA (3-300 microM), applied by superfusion, decreased the spontaneous firing activity of the neurones, hyperpolarized the membrane potential and produced an outward current. 3. These effects of L-DOPA were graded and were antagonized by sulpiride, a D2-receptor antagonist. 4. The L-DOPA activated membrane hyperpolarization persisted in slices exposed to tetrodotoxin while it was markedly reduced or abolished in solutions with no calcium plus cobalt (2 mM). 5. In slices treated with carbidopa, an inhibitor of the aromatic amino acid decarboxylase enzyme, the actions of L-DOPA were greatly reduced. 6. We propose that L-DOPA inhibits the firing of substantia nigra zona compacta neurones by being converted to dopamine which is then released by these cells.

1. Intracellular recordings were made from neurones in vitro in the rat substantia nigra zona compacta and ventral tegmental area; the neurones had the characteristic properties of dopamine-containing cells, and fired action potentials spontaneously. 2. Cocaine (1-10 microM) inhibited spontaneous firing, hyperpolarized the membrane and (in neurones voltage-clamped at -60 mV) caused an outward membrane current; the minimally effective concentration was 1 microM. These effects were blocked by sulpiride (30 nM-1 microM). 3. Dopamine (3-100 microM) also inhibited firing, hyperpolarized and caused an outward current. These effects of dopamine were potentiated about five fold by cocaine (10 microM). 4. It is concluded that cocaine (1-10 microM) inhibits the firing and hyperpolarizes substantia nigra zona compacta neurones in vitro by blocking the uptake of dopamine which the cells continuously release.

1. The effects of (+)-amphetamine (1-300 microM) applied by superfusion, on substantia nigra zona compacta neurones were studied in slices of the rat mesencephalon with intracellular recording techniques (current and voltage clamp mode). 2. Amphetamine inhibited the action potential discharge, hyperpolarized the cells and increased the membrane conductance. Under voltage clamp it produced an outward current. 3. The amphetamine outward current reversed at potentials negative to -100 mV (2.5 mM extracellular potassium) and was reduced by barium, (1 mM) suggesting an increased potassium conductance. 4. In slices treated with tetrodotoxin and calcium-free solution and added cobalt, amphetamine was still effective. 5. (-)-Sulpiride, (1 microM) a D2 antagonist, blocked the effects of both amphetamine and dopamine. 6. In slices treated for more than 3 h with 30 microM alpha-methyl-DL-tyrosine, an agent known to block the synthesis of dopamine, the action of amphetamine was attenuated, while dopamine was still effective. 7. Responses to applied dopamine were potentiated by cocaine (10 microM) but unaffected by amphetamine (1-3 microM). 8. It is suggested that the inhibition of substantia nigra compacta neurones by amphetamine is mainly due to the release of endogenous dopamine.