Experiences of access to healthcare among newly arrived immigrants in Denmark: Examining the role of residence permit.

AIMS: In Denmark, all residents regardless of nationality are 'de jure' entitled to a wide range of free-of-charge healthcare services. There is, however, only scarce quantitative knowledge on immigrants' experiences of their 'de facto' access to healthcare and on how access relates to immigrants' types of residence permits. The study aims to address these gaps. METHODS: Survey data on access to healthcare, employment and housing were collected among adult, newly arrived immigrants in Denmark (n=1711) at 26 publicly contracted Danish language schools in September-December 2021 by national cluster-random sampling stratified by region. Data were analysed using descriptive statistics and multivariate logistic regression. RESULTS: In total, 21% reported general difficulties obtaining good healthcare. Commonly experienced barriers related to financial constraints (39%), communication (37%) and lack of knowledge about the healthcare system (37%). Refugees and their families had higher odds of reporting barriers related to finances (odds ratio (OR) 2.58; confidence interval (CI) 1.77-3.76), communication (OR 3.15; CI 2.39-4.14) and knowledge (OR 1.84; CI 1.16-2.90), while other family reunified immigrants had lower odds of reporting knowledge barriers (OR 0.71; CI 0.54-0.93) compared with immigrants with EU/EEA residence permits, adjusted for gender and residential region. These results remained significant when further adjusted for age, length of stay, education, income, rural/urban residence and household size. CONCLUSIONS: Difficulties accessing healthcare are experienced by a large share of newly arrived immigrants in Denmark and are dependent on residence permit type. The findings suggest strengthened efforts to reduce barriers related to finances, communication and knowledge, while focusing on the most vulnerable immigrants.

The Amsterdam Sexual Abuse Case: What Scars did it Leave? Long-Term Course of Psychological Problems for Children Who have been Sexually Abused at a Very Young Age, and their Parents.

Longitudinal research of CSA in infancy and early childhood is scarce. The current study examined the long-term course of psychological outcomes (PTSD, dissociation and internalizing and externalizing behavioral problems) in children who were sexually abused in the early childhood. Additionally, we looked into the outcomes for their parents by assessing PTSD symptoms and negative emotional reactions towards the sexual abuse of their child. We examined the outcomes for five consecutive years in a sample of children (n = 45) who were sexually abused at a very young age (0-3) and their parents (n = 42), included in the Amsterdam Sexual Abuse Case-study. We found that outcomes following CSA in early childhood go beyond PTSD symptoms and can manifest in atypical symptoms such as behavioral problems. Parents experienced persistent PTSD in the years following CSA disclosure. CSA in very young children warrants long-term monitoring, as negative outcomes still present 8 years later.

Accuracy of the Diagnostic Infant and Preschool Assessment (DIPA) in a Dutch sample.

BACKGROUND: To prevent negative effects of early-onset psychiatric disorders on children's development, structured diagnostics are needed. However, validated diagnostic instruments (based on DSM-5) for children aged 7 years and younger are scarce. The Diagnostic Infant and Preschool Assessment (DIPA) is a diagnostic interview developed in the USA for measuring 16 psychiatric disorders in young children. The psychometric properties of the American version of the DIPA have been validated. Here we determined the accuracy of the psychometric properties of the Dutch DSM-5 based version of the DIPA for the corresponding population. MATERIAL AND METHODS: Psychometric properties of the DSM-5 based version of the DIPA were determined based on a sample of 136 biological, foster, therapeutic foster and adoptive parents of clinically referred children and children involved in a serious accident (aged 1-7 years). In line with the American validation study, we included the following seven DIPA modules: posttraumatic stress disorder (PTSD), major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), separation anxiety disorder (SAD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). We administered the DIPA, Trauma Symptom Checklist for Young Children (TSCYC) and Child Behavior Checklist (CBCL). Analyses were conducted with continuous outcomes (number of symptoms) and categorical outcomes (diagnoses). RESULTS: The Dutch DSM-5 based version of the DIPA showed good internal consistency and interrater reliability with both continuous and categorical variables. The concurrent validity was good; we found a good concordance between the DIPA and corresponding questionnaires on both the symptom and diagnoses level. In addition, the divergence on symptom level between the DIPA and non-corresponding questionnaires was adequate, which indicated adequate divergent validity. Due to a limited number of positive cases, we could not draw conclusions regarding its psychometric properties in the GAD and OCD modules. CONCLUSIONS: Our study shows promising initial results regarding the reliability and validity of the Dutch version of the DIPA, that is based on the DSM-5. Therefore, we recommend the use of the DIPA in research and clinical practice.

Short and Long-Term Parental Posttraumatic Stress After a Child's Accident: Prevalence and Associated Factors.

Studies on the long-term prevalence of parental posttraumatic stress symptoms (PTSS) following child accidental injury are scarce, and findings on risk factors vary. In this follow-up study (T2, n = 69) we determined the prevalence of parental PTSS 2-4 years after accidental injury of their child, compared with 3 months after the accident (T1, n = 135). Additionally, we examined the association between parental and child factors and PTSS severity. Children were 8-18 years old at the time of the accident. Parent and child PTSS was assessed by self-report. Other data were retrieved from medical records and a telephone interview. Parental PTSS was 9.6% at T1 and 5.8% at T2. Acute parental stress as measured within 2 weeks of the child's accident was significantly associated with parental PTSS severity (T1 and T2), as was the child's hospitalization of more than 1 day at T1 and the child's permanent physical impairment at T2. To prevent adverse long-term psychological consequences we recommend identifying and monitoring parents at risk and offering them timely treatment.

Long-Term Posttraumatic Stress Following Accidental Injury in Children and Adolescents: Results of a 2-4-Year Follow-Up Study.

In this study, we determined the long-term prevalence of posttraumatic stress disorder (PTSD) in children and adolescents after accidental injury and gained insight into factors that may be associated with the occurrence of PTSD. In a prospective longitudinal study, we assessed diagnosed PTSD and clinically significant self-reported posttraumatic stress symptoms (PTSS) in 90 children (11-22 years of age, 60% boys), 2-4 years after their accident (mean number of months 32.9, SD 6.6). The outcome was compared to the first assessment 3 months after the accident in 147 children, 8-18 years of age. The prevalence of PTSD was 11.6% at first assessment and 11.4% at follow-up. Children with PTSD or PTSS reported significantly more permanent physical impairment than children without. Children who completed psychotherapy had no symptoms or low levels of symptoms at follow-up. Given the long-term prevalence of PTSD in children following accidents, we recommend systematic monitoring of injured children. The role of possible associated factors in long-term PTSS needs further study.

The Association Between Acute Pain and Posttraumatic Stress Symptoms in Children and Adolescents 3 Months After Accidental Injury.

Previous research suggests that acute pain is a risk factor for later posttraumatic stress symptoms (PTSS). In a prospective cohort study, we examined the association between acute pain from accidental injury and PTSS in children and adolescents, taking into account factors potentially related to pain or posttraumatic stress. Participants were 135 children and adolescents, 8-18 years old. We measured the worst experienced pain since the accident took place with a visual analogue scale. Three months after the accident, posttraumatic stress was assessed with a self-report measure. We found a positive association between acute pain and posttraumatic stress. The amount of pain was negatively associated with injury severity in girls and positively associated with the presence of an extremity fracture in boys. In children who reported severe pain, this pain was significantly associated with PTSS and may account for around 10% of the variance in the severity of PTSS. Although the experience of pain is subjective, our study indicates that severe pain is associated with the severity of later PTSS. Timely management of pain according to acute pain protocols in all phases and disciplines after accidental injury is therefore recommended.

Increasing Resource Parents' Sensitivity towards Child Posttraumatic Stress Symptoms: a Descriptive Study on a Trauma-Informed Resource Parent Training.

Resource parents are often insufficiently prepared for recognizing and managing posttraumatic stress symptoms (PTSS) in their traumatized foster children, which can put a successful foster placement at risk. The Resource Parent Curriculum (RPC) developed by the National Child Traumatic Stress Network is designed to increase resource parents' sensitivity towards child PTSS. This study explores the effect of the RPC on resource parents' recognition of child PTSS, resource parents' perceived upbringing stress in caring for their foster child, and child PTSS before entering the RPC (T0), after completing the RPC (T1) and at six-month follow-up (T2). Results (n = 108) show an increase in recognition of child PTSS and a decrease in resource parents' experienced upbringing stress and child PTSS over time. Findings suggest that the RPC increases resource parents' trauma sensitivity. However, child PTSS severity remains high. To address foster children's PTSS, child trauma-focused treatment appears needed in addition to the RPC.

Predicting posttraumatic stress disorder in children and parents following accidental child injury: evaluation of the Screening Tool for Early Predictors of Posttraumatic Stress Disorder (STEPP).

BACKGROUND: Children and their parents are at risk of posttraumatic stress disorder (PTSD) following injury due to pediatric accidental trauma. Screening could help predict those at greatest risk and provide an opportunity for monitoring so that early intervention may be provided. The purpose of this study was to evaluate the Screening Tool for Early Predictors of Posttraumatic Stress Disorder (STEPP) in a mixed-trauma sample in a non-English speaking country (the Netherlands). METHODS: Children aged 8-18 and one of their parents were recruited in two academic level I trauma centers. The STEPP was assessed in 161 children (mean age 13.9 years) and 156 parents within one week of the accident. Three months later, clinical diagnoses and symptoms of PTSD were assessed in 147 children and 135 parents. We used the Anxiety Disorders Interview Schedule for DSM-IV - Child and Parent version, the Children's Revised Impact of Event Scale and the Impact of Event Scale-Revised. Receiver Operating Characteristic analyses were performed to estimate the Areas Under the Curve as a measure of performance and to determine the optimal cut-off score in our sample. Sensitivity, specificity, positive and negative predictive values were calculated. The aim was to maximize both sensitivity and negative predictive values. RESULTS: PTSD was diagnosed in 12% of the children; 10% of their parents scored above the cut-off point for PTSD. At the originally recommended cut-off scores (4 for children, 3 for parents), the sensitivity in our sample was 41% for children and 54% for parents. Negative predictive values were 92% for both groups. Adjusting the cut-off scores to 2 improved sensitivity to 82% for children and 92% for parents, with negative predictive values of 92% and 96%, respectively. CONCLUSIONS: With adjusted cut-off scores, the STEPP performed well: 82% of the children and 92% of the parents with a subsequent positive diagnosis were identified correctly. Special attention in the screening procedure is required because of a high rate of false positives. The STEPP appears to be a valid and useful instrument that can be used in the Netherlands as a first screening method in stepped psychotrauma care following accidents.

Comparing three diagnostic algorithms of posttraumatic stress in young children exposed to accidental trauma: an exploratory study.

BACKGROUND: Both the DSM-5 algorithm for posttraumatic stress disorder (PTSD) in children 6 years and younger and Scheeringa's alternative PTSD algorithm (PTSD-AA) aim to be more developmentally sensitive for young children than the DSM-IV PTSD algorithm. However, very few studies compared the three algorithms simultaneously. The current study explores diagnostic outcomes of the three algorithms in young child survivors of accidental trauma. METHODS: Parents of 98 young children (0-7 years) involved in an accident between 2006 and 2012 participated in a semi-structured telephone interview. Child posttraumatic stress symptoms (PTSS) were measured with the Anxiety Disorders Interview Schedule for DSM-IV-Child Version (ADIS-C/P), complemented with items from the Diagnostic Infant and Preschool Assessment (DIPA). Descriptive statistics were used to analyze the characteristics of the children, accident related information and PTS symptoms. We compared the three PTSD algorithms in order to explore the diagnostic outcomes. RESULTS: A total of 9 of the children (9.2 %) showed substantial PTSS. Of these children 2 met the criteria of all three algorithms, 7 met both the DSM-5 subtype for children 6 years and younger and the PTSD-AA algorithm, and 2 did not fully meet any of the algorithms (subsyndromal PTSD). CONCLUSIONS: For young children, the DSM-5 subtype for children 6 years and younger and the PTSD-AA algorithm appear to be better suited than the previous DSM-IV algorithm. It remains important that clinicians pay attention to children with subsyndromal PTSD.

Safinamide: from molecular targets to a new anti-Parkinson drug.

Ideal treatment in Parkinson's disease (PD) aims at relieving symptoms and slowing disease progression. Of all remedies, levodopa remains the most effective for symptomatic relief, but the medical need for neuroprotectant drugs is still unfulfilled. Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. Safinamide potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned rats. Safinamide has excellent bioavailability, linear kinetics, and is suitable for once-a-day administration. Therefore, safinamide may be used in PD to reduce l-dopa dosage and also represents a valuable therapeutic drug to test disease-modifying potential.

Anti-allodynic effect of NW-1029, a novel Na(+) channel blocker, in experimental animal models of inflammatory and neuropathic pain.

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na(+) currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.

Designing quality control for neonatal screening assays.

The purpose of neonatal screening is to find those that have a high risk for a disorder and therefore need further action for diagnosis and treatment. The separation of the high-risk and low-risk groups is typically achieved by establishing cut-off values for interpretation of the test result. The guidelines should preferably include both a low cut-off and a high cut-off value, with a grey zone between them. The width of the grey zone can be used for defining the quality required by the assay. The present work is based on the use of the EZ Rules software (from Westgard QC, Madison, WI), which automatically selects control rules. The user enters the needed parameters, such as the precision (as % CV) and bias of the assay. By using the grey zone as the medical decision interval the program will calculate possible control rules for the assay. The program was used to calculate the control rule for the AutoDELFIA neoTSH assay (from PerkinElmer Wallac, Turku, Finland). The grey zone was taken as 10 - 20 mU/L TSH, which is the recommendation of the American Academy of Pediatrics (Pediat. 91, 1203 - 1209). The entered parameters were: a total imprecision of 9%, which is typically seen with the AutoDELFIA neoTSH kit, a bias of 0% and a preanalytical variation of 20%. With the number of controls chosen as two, as often is used, a 1 3.0 s rule can be applied. The program also gives alternative control rules. Many laboratories lack a documented definition of the required quality, and tend to use a 2 SD control rule, which however leads to many unnecessary rejections. The EZ Rules program provides a tool for selection of QC rules. With the quality of the AutoDELFIA neoTSH kit two controls and a 1 3.0 s rule is sufficient. Runs are rejected only if one control out of two exceeds the 3.0 SD limit.

Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys.

NW-1015 is a novel Na+ and Ca2+ channel blocker with broad spectrum anticonvulsant activity and an excellent safety margin. As the compound also shows sigma-1 receptor ligand properties it was deemed important to determine whether it possesses anticonvulsant properties in primates without causing behavioral and EEG abnormalities. Thus, the effects of NW-1015 on limbic electrically-induced afterdischarge (AD) were evaluated in four cynomolgus monkeys, and its activity compared to a single effective dose of phenytoin (PHT). The four male cynomolgus monkeys were chronically implanted for EEG recordings, from cortex and limbic structures. AD was induced in limbic areas by electrical stimulation. The effects of NW-1015 on the duration and the behavioral component of the AD were randomly tested at doses from 25 to 75 mg/kg and compared with the effects of PHT 50 mg/kg. Similarly to PHT, 50 mg/kg of NW-1015 significantly shortened the EEG AD and almost abolished AD elicited behavioral seizure. Only the behavioral effects of AD were reduced after administration of 25 mg/kg p.o. NW-1015 did not cause EEG or interictal behavioral alterations at doses up to 75 mg/kg p.o. These data further confirm the broad-spectrum anticonvulsant activity and a good safety profile of NW-1015 even in a primate model of complex partial seizures and suggest that its affinity for sigma-1 receptors is behaviorally irrelevant.

Anticonvulsant activity of PNU-151774E in the amygdala kindled model of complex partial seizures.

PURPOSE: PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a novel antiepileptic drug (AED) with a broad spectrum of activity in a variety of chemically and mechanically induced seizures. The objective of this study was to evaluate the activity of PNU-151774E in the amygdala fully kindled rat model of complex partial seizures, and to compare its effects with those of carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), and gabapentin (GBP), drugs used to treat this disease state. METHODS: Male Wistar rats were stimulated daily through electrodes implanted in the amygdala with a threshold current until fully generalized seizures developed. The rats were then treated with various doses of a single compound. Control values for each rat and drug dose were determined after vehicle administration followed by electrical stimulation 1 day before drug treatment. RESULTS: PNU-151774E (1, 10, 30 mg/kg; i.p.) reduced the duration of behavioral seizures significantly and dose-dependently at doses starting from 1 mg/kg. Higher doses significantly reduced seizure severity and afterdischarge duration. In contrast, no dose-related effects were noted after administration of PHT, whereas after CBZ treatment, a plateau of activity was noted from the intermediate to higher doses. The effects of PNU-151774E were comparable to those of LTG and GBP. CONCLUSIONS: The activity shown by PNU-151774E at doses similar to those that are active in models of generalized seizures indicates that PNU-151774E would also have potential efficacy in the treatment of complex partial seizures.

Synthesis and preliminary biological evaluation of new alpha-amino amide anticonvulsants incorporating a dextromethorphan moiety.

Dextromethorphan 1 is an effective neuroprotectant in animal models of epilepsy and ischemia but showed side-effects during clinical trials limiting its potential use in a clinical setting. Here we describe the enantioselective and enantiospecific syntheses and the initial in vitro and in vivo biological evaluation of new hybrid structures between 1 and a previously disclosed alpha-amino amide anticonvulsant (3).

Brain-derived neurotrophic factor immunoreactivity in the limbic system of rats after acute seizures and during spontaneous convulsions: temporal evolution of changes as compared to neuropeptide Y.

Seizures increase the synthesis of brain-derived neurotrophic factor in forebrain areas, suggesting this neurotrophin has biological actions in epileptic tissue. The understanding of these actions requires information on the sites and extent of brain-derived neurotrophic factor production in areas involved in seizures onset and their spread. In this study, we investigated by immunocytochemistry the changes in brain-derived neurotrophic factor in the hippocampus, entorhinal and perirhinal cortices of rats at increasing times after acute seizures eventually leading to spontaneous convulsions. We also tested the hypothesis that seizure-induced changes in brain-derived neurotrophic factor induce later modifications in neuropeptide Y expression by comparing, in each instance, their immunoreactive patterns. As early as 100 min after seizure induction, brain-derived neurotrophic factor immunoreactivity increased in CA1 pyramidal and granule neurons and in cells of layers II-III of the entorhinal cortex. At later times, immunoreactivity progressively decreased in somata while increasing in fibres in the hippocampus, the subicular complex and in specific layers of the entorhinal and perirhinal cortices. Changes in neuropeptide Y immunoreactivity were superimposed upon and closely followed those of brain-derived neurotrophic factor. One week after seizure induction, brain-derived neurotrophic factor and neuropeptide Y immunoreactivities were similar to controls in 50% of rats. In rats experiencing spontaneous convulsions, brain-derived neurotrophic factor and neuropeptide Y immunoreactivity was strongly enhanced in fibres in the hippocampus/parahippocampal gyrus and in the temporal cortex. In the dentate gyrus, changes in immunoreactivity depended on sprouting of mossy fibres as assessed by growth-associated protein-43-immunoreactivity. These modifications were inhibited by repeated anticonvulsant treatment with phenobarbital. The dynamic and temporally-linked alterations in brain-derived neurotrophic factor and neuropeptide Y in brain regions critically involved in epileptogenesis suggest a functional link between these two substances in the regulation of network excitability.

Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound.

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy)benzylamino)propanamide methanesulfonate], a new anticonvulsant that displays a wide therapeutic window, has a potency comparable or superior to that of most classic anticonvulsants. PNU-151774E is chemically unrelated to current antiepileptics. In animal seizure models it possesses a broad spectrum of action. In the present study, the action mechanism of PNU-151774E has been investigated using electrophysiological and biochemical assays. Binding studies performed with rat brain membranes show that PNU-151774E has high affinity for binding site 2 of the sodium channel receptor, which is greater than that of phenytoin or lamotrigine (IC50, 8 microM versus 47 and 185 microM, respectively). PNU-151774E reduces sustained repetitive firing in a use-dependent manner without modifying the first action potential in hippocampal cultured neurons. In the same preparation PNU-151774E inhibits tetrodotoxin-sensitive fast sodium currents and high voltage-activated calcium currents under voltage-clamp conditions. These electrophysiological activities of PNU-151774E correlate with its ability to inhibit veratrine and KCl-induced glutamate release in rat hippocampal slices (IC50, 56.4 and 185.5 microM, respectively) and calcium inward currents in mouse cortical neurons. On the other hand, PNU-151774E does not affect whole-cell gamma-aminobutryic acid- and glutamate-induced currents in cultured mouse cortical neurons. These results suggest that PNU-151774E exerts its anticonvulsant activity, at least in part, through inhibition of sodium and calcium channels, stabilizing neuronal membrane excitability and inhibiting transmitter release. The possible relevance of these pharmacological properties to its antiepileptic potential is discussed.

PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat.

Kainic acid-induced multifocal status epilepticus in the rat is a model of medically intractable complex partial seizures and neurotoxicity. The exact mechanisms of kainic acid epileptogenic and neurotoxic effects are unknown, but enhanced glutamate release seems to be an important factor. PNU-151774E ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate) is a broad-spectrum new anticonvulsant with Na+ channel-blocking and glutamate release inhibiting properties. We have examined the effect of pretreatment with this compound on both seizure activity and hippocampal neuronal damage induced by systemic injection of kainic acid in rats. Lamotrigine, a recently developed anticonvulsant with similar glutamate release inhibitory properties, was tested for comparison, together with diazepam as reference standard, on the basis of its anticonvulsant and neuroprotectant properties in this animal model. PNU-151774E, lamotrigine (10, 30 mg/kg; i.p.) and diazepam (20 mg/kg; i.p.) were administered 15 min before kainic acid (10 mg/kg; i.p.). In the vehicle-treated group, kainic acid injection caused status epilepticus in 86% of animals. Hippocampal neuronal cell loss was 66% in the CA4 hippocampal area at 7 days after kainic acid administration. Diazepam inhibited both seizures and neurotoxicity. Lamotrigine reduced hippocampal neuronal cell loss at both doses, even when it did not protect from seizures, although it showed a trend toward protection. On the other hand PNU-151774E protected from both hippocampal neurodegeneration and status epilepticus. Thus, these data support the concept that seizure prevention and neuroprotection might not be tightly coupled. Glutamate release inhibition may play a major role in neuroprotection, but an additional mechanism(s) of action might be relevant for the anticonvulsant activity of PNU-151774E in this model.

Preclinical evaluation of PNU-151774E as a novel anticonvulsant.

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a structurally novel anticonvulsant having Na+ channel-blocking and glutamate release-inhibiting properties, as well as being a MAOB inhibitor. Its anticonvulsant activity was evaluated in the maximal electroshock (MES) test and in chemically induced seizures (bicuculline, BIC; picrotoxin, PIC; 3-mercaptopropionic acid, 3-MPA; pentylenetetrazole, PTZ; strychnine, STRYC). Behavioral toxicity was evaluated in the rotorod test with measurements of spontaneous locomotor activity and passive avoidance responding. The anti-MES activity of PNU-151774E in both mice and rats, respectively, produced ED50 values of 4.1 mg/kg and 6.9 mg/kg after i.p. administration or 8.0 mg/kg and 11.8 mg/kg after p.o. administration. Oral anti-MES activity in rats peaked between 1 and 2 h after administration and was evident up to 4 h. This activity was related to brain levels of unchanged drug which peaked at 37 mM within 1 h. Oral ED50 values (mg/kg) effective in blocking tonic extension seizures by chemical convulsants in mice were: BIC (26.9), PIC (60.6), 3-MPA (21.5), STRYC (104.1) and PTZ (26.8). This potency was associated with high therapeutic indices relative to: MES (78.2), BIC (23.3), PIC (10.3), 3-MPA (29.1) and STRYC (6.0). No evidence of tolerance to anti-MES activity after repeated dosing was observed. PNU-151774E did not show anti-absence seizure activity as assessed by i.v. infusion of PTZ. PNU-151774E impaired spontaneous activity in rats only at the oral rotorod ED50 dose of 700 mg/kg p.o. PNU-151774E did not impair passive avoidance responding at doses up to 40 times the oral MES ED50 dose in rats. These results indicate that PNU-151774E is an anticonvulsant effective in various seizure models with a wide therapeutic window, and with a low potential to induce tolerance and locomotor or cognitive side effects.

Long-term synaptic depression in the striatum: physiological and pharmacological characterization.

The effect of tetanic activation of corticostriatal glutamatergic fibers was studied in striatal slices by utilizing extracellular and intracellular recording techniques. Tetanic stimulation produced a long-term synaptic depression (LTD) (> 2 h) of both extracellularly recorded field potentials and intracellularly recorded EPSPs. LTD was not coupled with changes of intrinsic membrane properties of the recorded neurons. In some neurons, repetitive cortical activation produced a short-term posttetanic potentiation (1-3 min). Subthreshold tetanic stimulation, which under control condition did not cause LTD, induced LTD when associated with membrane depolarization. Moreover, LTD was not expressed in cells in which the conditioning tetanus was coupled with hyperpolarization of the membrane. Bath application of aminophosphonovalerate (30-50 microM), an antagonist of NMDA receptors, did not affect the amplitude of the synaptic potentials and the expression of LTD. Striatal LTD was significantly reduced by the pretreatment of the slices with 30 microM 2-amino-3-phosphonopropionic acid, an antagonist of glutamate metabotropic receptors. LTD was not blocked by bicuculline (30 microM), a GABA(A) receptor antagonist. Scopolamine (3 microM), an antagonist of muscarinic receptors, induced a slight, but significant, increase of the amplitude of LTD. Both SCH 23390 (3 microM), an antagonist of D1 dopamine (DA) receptors, and I-sulpiride (1 microM), an antagonist of D2 DA receptors, blocked LTD. LTD was also absent in slices obtained from rats in which the nigrostriatal DA system was lesioned by unilateral nigral injection of 6-hydroxydopamine. In DA-depleted slices, LTD could be restored by applying exogenous DA (30 microM) before the conditioning tetanus. In DA-depleted slices, LTD could also be restored by coadministration of SKF 38393 (3-10 microM), a D1 receptor agonist, and of LY 171555 (1-3 microM), a D2 receptor agonist. Application of a single class of DA receptor agonists failed to restore LTD. These data show that striatal LTD requires three main physiological and pharmacological conditions: (1) membrane depolarization and action potential discharge of the postsynaptic cell during the conditioning tetanus, (2) activation of glutamate metabotropic receptors, and (3) coactivation of D1 and D2 DA receptors. Striatal LTD may alter the output signals from the striatum to the other structures of the basal ganglia. This form of synaptic plasticity can influence the striatal control of motor activity.