Different roles of T-type calcium channel isoforms in hypnosis induced by an endogenous neurosteroid epipregnanolone.

BACKGROUND: Many neuroactive steroids induce sedation/hypnosis by potentiating γ-aminobutyric acid (GABAA) currents. However, we previously demonstrated that an endogenous neuroactive steroid epipregnanolone [(3ß,5ß)-3-hydroxypregnan-20-one] (EpiP) exerts potent peripheral analgesia and blocks T-type calcium currents while sparing GABAA currents in rat sensory neurons. This study seeks to investigate the behavioral effects elicited by systemic administration of EpiP and to characterize its use as an adjuvant agent to commonly used general anesthetics (GAs). METHODS: Here, we utilized electroencephalographic (EEG) recordings to characterize thalamocortical oscillations, as well as behavioral assessment and mouse genetics with wild-type (WT) and different knockout (KO) models of T-channel isoforms to investigate potential sedative/hypnotic and immobilizing properties of EpiP. RESULTS: Consistent with increased oscillations in slower EEG frequencies, EpiP induced an hypnotic state in WT mice when injected alone intra-peritoneally (i.p.) and effectively facilitated anesthetic effects of isoflurane (ISO) and sevoflurane (SEVO). The CaV3.1 (Cacna1g) KO mice demonstrated decreased sensitivity to EpiP-induced hypnosis when compared to WT mice, whereas no significant difference was noted between CaV3.2 (Cacna1h), CaV3.3 (Cacna1i) and WT mice. Finally, when compared to WT mice, onset of EpiP-induced hypnosis was delayed in CaV3.2 KO mice but not in CaV3.1 and CaV3.3 KO mice. CONCLUSION: We posit that EpiP may have an important role as novel hypnotic and/or adjuvant to volatile anesthetic agents. We speculate that distinct hypnotic effects of EpiP across all three T-channel isoforms is due to their differential expression in thalamocortical circuitry.

Characterization of pharmaco-EEG fingerprint and sleep-wake profiles of Lavandula angustifolia Mill. essential oil inhalation and diazepam administration in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lavandula angustifolia Mill. Essential oil (Lavender EO) has a long history of medicinal use and is particularly claimed to possess anxiolytic and sedative properties. Lavender EO aromatherapy has been used to reduce distress and improve insomnia naturally. Increasing evidence appeared to show similarities between the effects of lavender EO and the anxiolytic drugs, benzodiazepines. However, its effects on sleep-wake and electrical brain patterns in comparison to that of the standard anxiolytic, diazepam, remained to be explored. AIM OF THE STUDY: The aim of this work was to investigate electroencephalography (EEG) profiles and sleep-pattern elicited by lavender EO inhalation compared to that of diazepam, a standard anxiolytic drug in in vivo rat model. MATERIALS AND METHODS: Adult male Wistar rats were anesthetized for electrode implantation on the frontal and parietal skulls. EEG signals were recorded for 180 min following intraperitoneal injection of diazepam (10 mg/kg) or during continuous inhalation of lavender EO (200 µL) or distilled water (control). Fast Fourier transform was used for the analyses of EEG power spectra and sleep-wake parameters. RESULTS: During a 30-60 min period, diazepam and lavender EO significantly increased frontal powers of 0.78-45.31 and 7.03-18.36 Hz, respectively. Both treatments also increased parietal powers with lower magnitudes of significant change. Significant increases in some frequency ranges remained until a 60-90 min period. Sleep-wake analyses also revealed that diazepam significantly reduced time spent in wake, increased time spent in non-rapid eye movement (NREM), increased episode duration of NREM, decreased numbers of wake episode and decreased rapid eye movement (REM) sleep latency. On the other hand, lavender EO only significantly decreased wake episodes and latency to REM sleep. Lavender EO inhalation reduced numbers of wake episode but maintain normal time spent in wake, NREM and REM sleeps. CONCLUSIONS: These findings might suggest beneficial and distinct anxiolytic-like effects of lavender EO for sleep enhancing purposes.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development.

The effects of chronic mitragynine (Kratom) exposure on the EEG in rats.

Mitragynine is the main alkaloid isolated from the leaves of Mitragyna speciosa Korth (Kratom). Kratom has been widely used to relieve pain and opioid withdrawal symptoms in humans but may also cause memory deficits. Here we investigated the changes in brain electroencephalogram (EEG) activity after acute and chronic exposure to mitragynine in freely moving rats. Vehicle, morphine (5 mg/kg) or mitragynine (1, 5 and 10 mg/kg) were administered for 28 days, and EEG activity was repeatedly recorded from the frontal cortex, neocortex and hippocampus. Repeated exposure to mitragynine increased delta, but decreased alpha powers in both cortical regions. It further decreased delta power in the hippocampus. These findings suggest that acute and chronic mitragynine can have profound effects on EEG activity, which may underlie effects on behavioral activity and cognition, particularly learning and memory function.

APOE genotype influences P3b amplitude and response to smoking abstinence in young adults.

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.

Pharmacological and toxicological effects of Ruta chalepensis L. on experimentally induced seizures and electroencephalographic spectral power in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ruta chalepensis L. (Rutaceae) is used in traditional medicine to treat a wide variety of disorders such as rheumatism, fever, mental disorders, dropsy, neuralgia, menstrual problems, anxiety, and epilepsy. AIM OF THE STUDY: To evaluate and compare the anticonvulsant properties of an aqueous extract and ethyl acetate (AcOEt) fraction of R. chalepensis on pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) test in mice, by analyzing behavior and electroencephalogram (EEG), as well as GABAA receptors involvement. METHODS: The effect of an acute administration of different dosage of the aqueous extract (300 or 500 mg/kg) or AcOEt fraction (100, 300, 500 or 1000 mg/kg) of R. chalepensis was explored on two different models of acute seizure induction in mice, the PTZ and maximal electroshock (MES) tests. Behavioral and electrographic effects were quantified. Additionally, the possible involvement of the GABAA receptors was explored in the presence of picrotoxin (a non-competitive antagonist of the GABAA receptor). RESULTS: AcOEt fraction of R. chalepensis was more efficient than aqueous extract to reduce the incidence of tonic-clonic seizures and mortality in a significant and dose-dependent manner in both the PTZ and MES tests. This anticonvulsant effect was not abolished in the presence of picrotoxin. The EEG spectral power analysis revealed that aqueous extract decreased alpha and beta power, while AcOEt fraction decreased alpha and gamma power confirming previous findings of its depressant effect in the central nervous system. It is important to mention that the highest dosage of the AcOEt (1000 mg/kg) produced a severe suppression or isoelectric EEG activity (EEG flattening), recognized as a comatose state, suggesting a neurotoxic effect at this dosage. CONCLUSION: Our data reinforce that depressant and anticonvulsant effects of R. chalepensis depend in part on the presence of constituents from medium polarity. We also found that anticonvulsant effect is not mediated by GABAA receptors. In addition, cautious is emphasized when high doses of this natural product are used in traditional medicine since it might produce neurotoxic effects.

Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy.

Epileptogenesis, the gradual process that leads to epilepsy after brain injury or genetic mutations, is a complex network phenomenon, involving a variety of morphological, biochemical and functional brain alterations. Although risk factors for developing epilepsy are known, there is currently no treatment available to prevent epilepsy. We recently proposed a multitargeted, network-based approach to prevent epileptogenesis by rationally combining clinically available drugs and provided first proof-of-concept that this strategy is effective. Here we evaluated eight novel rationally chosen combinations of 14 drugs with mechanisms that target different epileptogenic processes. The combinations consisted of 2-4 different drugs per combination and were administered systemically over 5 days during the latent epileptogenic period in the intrahippocampal kainate mouse model of acquired temporal lobe epilepsy, starting 6 h after kainate. Doses and dosing intervals were based on previous pharmacokinetic and tolerability studies in mice. The incidence and frequency of spontaneous electrographic and electroclinical seizures were recorded by continuous (24/7) video linked EEG monitoring done for seven days at 4 and 12 weeks post-kainate, i.e., long after termination of drug treatment. Compared to vehicle controls, the most effective drug combination consisted of low doses of levetiracetam, atorvastatin and ceftriaxone, which markedly reduced the incidence of electrographic seizures (by 60%; p<0.05) and electroclinical seizures (by 100%; p<0.05) recorded at 12 weeks after kainate. This effect was lost when higher doses of the three drugs were administered, indicating a synergistic drug-drug interaction at the low doses. The potential mechanisms underlying this interaction are discussed. We have discovered a promising novel multitargeted combination treatment for modifying the development of acquired epilepsy.

Gastrodin alleviates seizure severity and neuronal excitotoxicities in the rat lithium-pilocarpine model of temporal lobe epilepsy via enhancing GABAergic transmission.

ETHNOPHARMACOLOGICAL RELEVANCE: Temporal lobe epilepsy remains one of the most drug-resistant focal epilepsy, leading to enormous healthcare burden. Among traditional herb medicine, some ingredients have the potential to treat seizure and alleviate the neuronal excitoxicity. The dried rhizome of Gastrodia elata Blume has been used to treat convulsive disorder, dizziness, dementia and migraine in eastern Asia. AIM OF THE STUDY: To determine whether gastrodin, an active ingredient of Gastrodia elata Blume, can reduce lithium-pilocarpine induced seizure severity and neuronal excitotoxicity and explore the underlying mechanism. MATERIALS AND METHODS: We divided the Sprague-Dawley rats into an experimental group (gastrodin group) and a control group (Dimethyl sulfoxide, vehicle group) and performed the behavioral analysis and electroencephalography to determine the effect of gastrodin on the seizure severity induced by lithium-pilocarpine injection. Nissl-stained histopathology elucidated the degree of rat hippocampal neuronal damage as markers of acute and subacute neuronal excitotoxicity. Besides, the Western blotting of dissected hippocampus was carried out to demonstrate the protein expression involving GABAergic transmission and metabolic pathway. RESULTS: Gastrodin reduced the acute seizure severity in lithium-pilocarpine-induced seizure model. In electroencephalography recording, gastrodin exerted inhibitory action on epileptiform discharge. Compared with control group, gastrodin exhibited neuroprotective effect against seizure related hippocampal neuronal damage at acute and subacute stages. The Western blotting showed that gastrodin reversed the degradation of GABAA receptor after pilocarpine-induced seizures. CONCLUSIONS: In the experimental seizure model, gastrodin showed anti-seizure and neuroprotective abilities. Enhancing the expression of GABAA receptor plays an important role in its antiepileptic mechanism. The results offer a new insight of developing new antiepileptic drugs from traditional Chinese medicine.

Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial / Efeito da pré‐ administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado

Abstract Background and objectives Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol. Methods Ninety-six patients (ASA I or II, aged 18-65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5 mg.kg−1, 0.75 mg.kg−1 and 1 mg.kg−1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The "up-and-down" method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 µg.mL−1-lower (or -higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation and 15 minutes after intubation. Results The EC50 of propofol was lower in Group C (2.32 µg.mL−1, 95% Confidence Interval [95% CI] 1.85-2.75) and D (2.39 µg.mL−1, 95% CI 1.91-2.67) than in Group A (2.96 µg.mL−1, 95% CI 2.55-3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 µg.mL−1, 95% CI 2.33-2.71) and Group A (p > 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05). Conclusion High-dose FA (0.75 mg.kg−1 or 1 mg.kg−1) reduces the EC50 of propofol, and 1 mg.kg−1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.

Resumo Justificativa e objetivos A administração pré‐operatória de Flurbiprofeno Axetil (FA) é amplamente usada para a modulação da analgesia. No entanto, a relação entre FA e fármacos sedativos permanece obscura. Neste estudo, nosso objetivo foi investigar os efeitos de diferentes doses de FA na Concentração Efetiva mediana (CE50) do propofol. Métodos Noventa e seis pacientes (ASA I ou II, com idades de 18-65 anos) foram alocados aleatoriamente em quatro grupos na proporção de 1:1:1:1. Dez minutos antes da indução, o Grupo A (grupo controle) recebeu 10 mL de Intralipid, enquanto os grupos B, C e D receberam FA na dose de 0,5 mg.kg‐1; 0,75 mg.kg‐1 e 1 mg.kg‐1, respectivamente. A profundidade da anestesia foi medida pelo Índice Bispectral (BIS). O método up‐and‐down foi usado para calcular a CE50 do propofol. Durante o período de equilíbrio, se o valor do BIS fosse ≤ 50 ou BIS > 50, o próximo paciente tinha a infusão de propofol ajustada para uma concentração alvo‐controlada 0,5 µg.mL‐1 inferior ou superior, respectivamente. Os dados hemodinâmicos foram registrados no início do estudo, 10 minutos após a administração de FA, após a indução, após a intubação e 15 minutos após a intubação. Resultados A CE50 do propofol foi menor no Grupo C (2,32 µg.mL‐1, Intervalo de Confiança de 95% [95% IC] 1,85-2,75) e D (2,39 µg.mL‐1, 95% IC 1,91-2,67) do que no Grupo A (2,96 µg.mL‐1; 95% IC 2,55-3,33) (p = 0,023, p = 0,048, respectivamente). Não houve diferenças significantes na CE50 entre o Grupo B (2,53 µg.mL‐1, 95% IC 2,33-2,71) e o Grupo A (p > 0,05). Não houve diferenças significantes na Frequência Cardíaca (FC) entre os grupos A, B e C. A FC foi significantemente menor no grupo D do que no grupo A após a intubação (66 ± 6 vs. 80 ± 10 bpm, p < 0,01) e 15 minutos após a intubação (61 ± 4 vs. 70 ± 8 bpm, p < 0,01). Não houve diferenças significantes entre os quatro grupos na Pressão Arterial Média (PAM) em qualquer momento. A PAM dos quatro grupos foi significantemente menor após a indução, após a intubação e 15 minutos após a intubação do que na linha de base (p < 0,05). Conclusão FA em altas doses (0,75 mg.kg‐1 ou 1 mg.kg‐1) reduz a CE50 do propofol, e 1 mg.kg‐1 de FA reduz a FC durante níveis adequados de anestesia em pacientes não estimulados. Embora esse resultado deva ser investigado na presença de estimulação cirúrgica, sugerimos que a pré‐administração de FA pode reduzir a necessidade de propofol durante anestesia cuja profundidade seja monitorada pelo BIS.

[Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial]. / Efeito da pré­administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado.

BACKGROUND AND OBJECTIVES: Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol. METHODS: Ninety-six patients (ASA I or II, aged 18-65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5 mg.kg-1, 0.75 mg.kg-1 and 1 mg.kg-1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The "up-and-down" method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 µg.mL-1-lower (or-higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation, and 15 minutes after intubation. RESULTS: The EC50 of propofol was lower in Group C (2.32 µg.mL-1, 95% Confidence Interval [95% CI] 1.85-2.75) and D (2.39 µg.mL-1, 95% CI 1.91-2.67) than in Group A (2.96 µg.mL-1, 95% CI 2.55-3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 µg.mL-1, 95% CI 2.33-2.71) and Group A (p ˃ 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05). CONCLUSION: High-dose FA (0.75 mg.kg-1 or 1 mg.kg-1) reduces the EC50 of propofol, and 1 mg.kg-1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.

Immediate versus late effects of vigabatrin on spike and wave discharges.

Vigabatrin increases GABA concentrations by inhibiting GABA transaminase. In previous studies, it was shown that vigabatrin increases the incidence of Spike and Wave Discharges (SWD) in the WAG/Rij rat model for absence epilepsy. Since following a single dose of vigabatrin GABA concentrations are known to be increased for several days, the present study sheds light on how the previously described changes in SWD characteristics develop over a longer time frame. To achieve this, we injected adult WAG/Rij rats with 500 mg/kg and recorded their EEG for 48 h. SWD were quantified, and their peak frequencies were calculated. Our results showed three rapid onset effects: a sharp increase in SWD incidence, from 12.5 /hour to 133/hour), this increase lasted only 4.4 h, an increase in mean SWD duration, from 4.6 s to 8.1 s and a drop in peak frequency, from 8 to 6 Hz. Since it takes several hours before GABA concentrations are sufficiently increased, we propose that these immediate effects are caused by direct stimulation of both GABAA and GABAB receptors by the molecule vigabatrin. Next, the mean SWD duration decreased below baseline values after 4.4 h. Hazard rate analysis showed that this is caused by an increased probability of short SWD. We argue that these changes are caused by increased activation of both GABAA and GABAB receptors in the frontal cortex and the thalamus, and more specifically, in the Reticular Thalamic Nucleus (RTN). After approximately 34 h, the probability of short SWD returned to normal. This suggests the occurrence of downregulation of GABA receptors. The decrease in peak frequency was still present 48 h after injection. It has been argued that the balance between GABAA and GABAB receptor-mediated activity in the RTN is crucial for controlling this SWD characteristic. It can be concluded that a single dose of vigabatrin results in remarkable and opposite effects over time: an initial, proabsence effect is followed by an antiabsence effect.

Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice.

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs.

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model.

With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (HT+V; n = 7); (iii) HT + Melatonin (HT+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after HI. Comparing HT+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/exchangeable phosphate were higher at 48 h in HT+M versus HT (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in HT+M (47.1 cells/mm2) compared to HT (123.8 cells/mm2) (p = 0.0003) and HT+V (97.5 cells/mm2) compared to HT (p = 0.012). Localized protection was seen in white matter for HT+M versus HT (p = 0.036) and internal capsule for HT+M compared to HT (p = 0.001) and HT+V versus HT (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.

Intraperitoneal injection of ginkgolide B, a major active compound of Ginkgo biloba, dose-dependently increases the amount of wake and decreases non-rapid eye movement sleep in C57BL/6 mice.

The terpene lactones of Ginkgo biloba extract, namely ginkgolides (A, B, and C) and bilobalide, possess antioxidant, anti-inflammatory, and neuroprotective effects. They are widely prescribed for the treatment of cerebral dysfunctions and neurological impairments. In addition, they demonstrate antagonistic action at the gamma-aminobutyric acid type A and glycine receptors, which are members of the ligand-gated ion channel superfamily. In the present study, the effects of ginkgolides (A, B, and C) and bilobalide on sleep in C57BL/6 mice were investigated. Ginkgolide B was found to dose-dependently increase the amount of wake and decrease that of non-rapid eye movement sleep without changes in the electroencephalography power density of each sleep/wake stage, core body temperature and locomotor activity for the first 6 h after intraperitoneal injection. Of note, the amount of wake after injection of 5 mg/kg of ginkgolide B showed a significant increase (14.9 %) compared with that of vehicle (P = 0.005). In contrast, there were no significant differences in the amount of sleep, core body temperature, and locomotor activity in the mice injected with ginkgolide A and C. Bilobalide briefly induced a decrease in locomotor activity but did not exert significant effects on the amounts of sleep and wake. The modes of action of the wake-enhancing effects of ginkgolide B are unknown. However, it may act through the antagonism of gamma-aminobutyric acid type A and glycine receptors because it is established that these inhibitory amino acids mediate sleep and sleep-related physiology. It is of interest to further evaluate the stimulant and awaking actions of ginkgolide B on the central nervous system in clinical and basic research studies.

Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation.

OBJECTIVE: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation. METHODS: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation. RESULTS: Among 1320 compounds, multiple candidates enhanced GABRB3 channel conductance in cell models. Vinpocetine, an alkaloid derived from the periwinkle plant with anti-inflammatory properties and the ability to modulate sodium and channel channels, was the lead candidate based on efficacy and safety profile. Vinpocetine was administered as a dietary supplement over 6 months, reaching a dosage of 20 mg three times per day, and resulted in a sustained, dose-dependent reduction in spike-wave discharge frequency on electroencephalograms. Improved language and behavior were reported by family, and improvements in global impression of change surveys were observed by therapists blinded to intervention. SIGNIFICANCE: Vinpocetine has potential efficacy in treating patients with this mutation and possibly other GABRB3 mutations or other forms of epilepsy. Additional studies on pharmacokinetics, potential drug interactions, and safety are needed.

Effect of Ibuprofen on Autophagy of Astrocytes During Pentylenetetrazol-Induced Epilepsy and its Significance: An Experimental Study.

Epilepsy is a chronic neurological disease. Astrogliosis is an important pathological change in epileptic lesions. Studies have reported that ibuprofen can affect autophagy and/or inhibit cell proliferation in many diseases. This study investigated the effect and significance of ibuprofen on autophagy of astrocytes during pentylenetetrazol (PTZ) induced epilepsy. 60 male Sprague-Dawley (SD) rats were randomly divided into five groups: control group (received normal saline), PTZ group, 3-methyladenine (3-MA) + PTZ group, ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group. Dose of each agent was 35 mg/kg (PTZ), 10 mg/kg (3-MA) and 30 mg/kg (ibuprofen) and all drugs were administered intraperitoneally 15 times on alternate days (29 days). Human astrocytes were cultured in vitro. Behavioral performance (i.e., latency, grade and duration of seizures) and EEG of rats were observed and recorded. Proliferation of astrocytes was detected by CCK-8 method. Immunofluorescence and Western blot test were used to detect the expression of LC3 and GFAP. Mean number, grade and duration of seizures were markedly reduced in ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group (P < 0.05). Similarly, peak of EEG waves were markedly reduced in ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group (P < 0.05). Compared to the control group, the level of LC3 in ibuprofen group was significantly increased in vitro (P < 0.05). While, levels of LC3 were significantly higher and that of GFAP were significantly lower in ibuprofen + PTZ group (P < 0.05) compared to PTZ group in vivo. Ibuprofen reduces the proliferation of astrocytes by increasing autophagy, thus affecting the development of epilepsy. Therefore, ibuprofen may be used as an adjuvant to improve efficacy of treatment in epilepsy.

The impact of frying aerosol on human brain activity.

Knowledge on the impact of the exposure to indoor ultrafine particles (UFPs) on the human brain is restricted. Twelve non-atopic, non-smoking, and healthy adults (10 female and 7 male, in average 22 years old) were monitored for brain physiological responses via electroencephalographs (EEGs) during cooking. Frying ground beef meat in sunflower oil using electric stove without ventilation was conducted. UFPs, particulate matter (PM) (PM1, PM2.5, PM4, PM10), CO2, indoor temperature, RH, oil and meat temperatures were monitored continuously throughout the experiments. The UFP peak concentration was recorded to be approximately 2.0 × 105 particles/cm3. EEGs were recorded before exposure, at end of cooking when PM peak concentrations were observed, and 30 min after the end of the cooking session (post-exposure). Brain electrical activity statistically significantly changed during post-exposure compared to the before exposure, suggesting the translocation of UFPs to the brain, occurring solely in the frontal and temporal lobes of the brain. Study participants older than 25 were more susceptible to UFPs compared to those younger than 25. Also, the brain abnormality was mainly driven by male rather than female study participants. The brain slow-wave band (delta) decreased while the fast-wave band (Beta3) increased similar to the pattern found in the literature for the exposure to smoking fumes and diesel exhaust.

Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model.

RATIONALE: Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance. OBJECTIVES: To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition. METHODS: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP. RESULTS: Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. CONCLUSIONS: These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study.

OBJECTIVE: This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. METHODS: Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. RESULTS: The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma ß-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. CONCLUSION: Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.