Prefoldins are novel regulators of the unfolded protein response in artemisinin resistant Plasmodium falciparum malaria.

Emerging Artemisinin (ART) resistance in Plasmodium falciparum (Pf) poses challenges for the discovery of novel drugs to tackle ART-resistant parasites. Concentrated efforts toward the ART resistance mechanism indicated a strong molecular link of ART resistance with upregulated expression of unfolded protein response pathways involving Prefoldins (PFDs). However, a complete characterization of PFDs as molecular players taking part in ART resistance mechanism, and discovery of small molecule inhibitors to block this process have not been identified to date. Here, we functionally characterized all Pf Prefoldin subunits (PFD1-6) and established a causative role played by PFDs in ART resistance by demonstrating their expression in intra-erythrocytic parasites along with their interactions with Kelch13 protein through immunoprecipitation coupled MS/MS analysis. Systematic biophysical interaction analysis between all subunits of PFDs revealed their potential to form a complex. The role of PFDs in ART resistance was confirmed in orthologous yeast PFD6 mutants, where PfPFD6 expression in yeast mutants reverted phenotype to ART resistance. We identified an FDA-approved drug "Biperiden" that restricts the formation of Prefoldin complex and inhibits its interaction with its key parasite protein substrates, MSP-1 and α-tubulin-I. Moreover, Biperiden treatment inhibits the parasite growth in ART-sensitive Pf3D7 and resistant Pf3D7k13R539T strains. Ring survival assays that are clinically relevant to analyze ART resistance in Pf3D7k13R539T parasites demonstrate the potency of BPD to inhibit the growth of survivor parasites. Overall, our study provides the first evidence of the role of PfPFDs in ART resistance mechanisms and opens new avenues for the management of resistant parasites.

Cholinergic modulation of motor sequence learning.

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double-blind placebo-controlled crossover design, we tested 30 healthy young participants and showed that biperiden impairs the ability to learn sequential finger movements, accompanied by widespread oscillatory broadband power changes (4-25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha and beta bands over ipsilateral motor and bilateral parietal-occipital areas. The reduced early theta power during a repeated compared with random sequence, likely reflecting disengagement of top-down attention to sensory processes, was disrupted by biperiden. Alpha synchronization during repeated sequences reflects sensory gating and lower visuospatial attention requirements compared with visuomotor responses to random sequences. After biperiden, alpha synchronization was greater, potentially reflecting excessive visuospatial attention reduction, affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing repeated sequences and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning.

Green spectrophotometric and spectrofluorimetric determination of biperiden hydrochloride using erythrosine B sensing probe.

Erythrosine B (EB) is a food colorant antiviral xanthene dye that has many applications as a color additive in pharmaceuticals and cosmetics. Its use as a sensor for spectrofluorimetric and spectrophotometric analysis of amine-based pharmaceuticals renders many advantages because of its availability, low cost, rapid labeling, and high sensitivity. Herein, two fast and sensitive spectrofluorimetric and spectrophotometric methods were established for the estimation of the anti-Parkinson drug, biperiden (BIP) hydrochloride (HCl), in its raw material and tablet forms. The proposed methods depended on the interaction between the phenolic group of EB and the tertiary amino group of the studied analyte to form an ion-pair complex at pH 4 using the Britton Robinson buffer. The spectrofluorimetric method is based on the measurement of the quenching power of BIP HCl on the fluorescence intensity of EB at λex/em = 527.0/550.9 nm. This method was rectilinear over the concentration range of 0.1-1.0 µg/mL with a limit of detection (LOD) = 0.017 µg/mL and a limit of quantification (LOQ) = 0.05 µg/mL. Meanwhile, the colorimetric method involved monitoring the absorbance of the formed ion-pair complex at 555 nm, showing a linearity range of 0.4-5.0 µg/mL with LOD = 0.106 µg/mL and LOQ = 0.322 µg/mL. The proposed methods were assessed for the greenness, indicating the greenness of the developed methods.

Preliminary investigation of the administration of biperiden to reduce relapses in individuals with cocaine/crack user disorder: A randomized controlled clinical trial.

BACKGROUND: Several studies have demonstrated that ACh modulates the dopaminergic circuit in the nucleus accumbens, and its blockade appears to be associated with the inhibition of the reinforced effect or the increase in dopamine caused by cocaine use. The objective of this study was to evaluate the effect of biperiden (a muscarinic receptor antagonist with a relatively higher affinity for the M1 receptor) on crack/cocaine use relapse compared to a control group that received placebo. METHODS: This study is a double-blind, randomized, placebo-controlled clinical trial. The intervention group received 2 mg of biperiden, 3 times a day, for a period of 3 months. The control group received identical placebo capsules, at the same frequency and over the same period. All participants were followed for a period of six months. RESULTS: The sample comprised 128 people, with 61 in the control group and 67 in the biperiden group. Lower substance consumption was observed in the group that received biperiden treatment two (bT2 = -2.2 [-3.3; -1.0], p < 0.001) and six months (bT4 = -6, 2 [-8.6; -3.9], p < 0.001) after the beginning of the intervention. The biperiden group had a higher latency until a possible first day of consumption, in the same evaluation periods (bT2 = 0.26 [0.080; 0.44], p = 0.004; bT4 = 0.63 [0.32; 0.93], p < 0.001). CONCLUSIONS: Despite the major limitations of the present study, the group that received biperiden reduced the number of days of cocaine/crack use and showed an increase in the latency time for relapse. More studies are needed to confirm the utility of this approach.

Biperiden reverses the increase in 50-kHz ultrasonic vocalizations but not the increase in locomotor activity induced by cocaine.

Cocaine use disorder (CUD) is a worldwide public health problem, associated with severe psychosocial and economic impacts. Currently, no FDA-approved treatment is available for CUD. However, an emerging body of evidence from clinical and preclinical studies suggests that biperiden, an M1 muscarinic receptor antagonist, presents potential therapeutic use for CUD. These studies have suggested that biperiden may reduce the reinforcing effects of cocaine. It is well established that rodents emit 50-kHz ultrasonic vocalizations (USV) in response to natural rewards and stimulant drugs, including cocaine. Nonetheless, the effects of biperiden on the cocaine-induced increase of 50-kHz USV remains unknown. Here, we hypothesized that biperiden could antagonize the acute effects of cocaine administration on rat 50-kHz USV. To test this hypothesis, adult male Wistar rats were divided into four experimental groups: saline, 5 mg/kg biperiden, 10 mg/kg cocaine, and biperiden/cocaine (5 and 10 mg/kg, i.p., respectively). USV and locomotor activity were recorded in baseline and test sessions. As expected, cocaine administration significantly increased the number of 50-kHz USV. Biperiden administration effectively antagonized the increase in 50-kHz USV induced by cocaine. Cocaine administration also increased the emission of trill and mixed 50 kHz USV subtypes and this effect was antagonized by biperiden. Additionally, we showed that biperiden did not affect the cocaine-induced increase in locomotor activity, although biperiden administration per se increased locomotor activity. In conclusion, our findings indicate that administering biperiden acutely reduces the positive affective effects of cocaine, as demonstrated by its ability to inhibit the increase in 50-kHz USV.

Dyskinesia due to mexiletine overdose: a rare presentation.

BACKGROUND: Mexiletine, a class IB antiarrhythmic, is a structural analog of lidocaine. Our knowledge of mexiletine overdose is based on lidocaine overdose reports. Only a few cases of mexiletine overdose have been reported, including fatal overdoses. Mexiletine toxicity primarily affects the central nervous, cardiovascular, and gastrointestinal systems. CASE: A 16-year-old female was brought to our hospital by ambulance after taking an unknown dose of mexiletine in a suicide attempt. Ventricular fibrillation developed while in the ambulance; cardiopulmonary resuscitation was started and spontaneous circulation returned within 1 min. The patient had been taking oral mexiletine for 1 month to treat primary erythromelalgia. Her vital signs were normal, but she was unconscious. Following gastric lavage she was transferred to the pediatric intensive care unit. Midazolam and levetiracetam were required due to uncontrolled seizures. During the first hour of hospitalization, severe dyskinesia characterized by abnormal involuntary large hyperkinetic movements in all 4 extremities was observed and successfully treated with 2 doses of intravenous biperiden. The patient was discharged on day 6 of hospitalization. CONCLUSIONS: Mexiletine overdose can be life-threatening. In addition to rapid and effective resuscitation, rapid identification and management of cardiovascular and central nervous system manifestations are key to preventing morbidity and mortality. The presented case had severe dyskinesia that was successfully treated with repeated doses of biperiden. Biperiden did not cause arrhythmia. Based on the presented case, we think biperiden should be considered for the treatment of movement disorders in cases of mexiletine overdose.

A novel method for the therapeutic drug monitoring of biperiden in plasma by GC-MS using salt-assisted liquid-liquid microextraction.

Biperiden is an anticholinergic agent with central effects. It is used in Parkinson's syndromes and in the treatment of extrapyramidal symptoms that occur with the use of various agents (neuroleptics, antipsychotics). It causes anticholinergic syndrome in high doses. For this reason, therapeutic drug monitoring of biperiden is important. This study, it was aimed to develop a validated GC-MS method for the therapeutic monitoring of biperiden in human plasma. Biperiden and internal standard biperiden-d5 were extracted from plasma using the salt-assisted liquid-liquid extraction method. The method was validated according to the European Medicines Agency (EMA), Bioanalytical method validation guidelines. The lower limit of quantification of the developed method was chosen as 0.5 ng/mL. The calibration curve of biperiden for the method was validated between 0.5 and 15 ng/mL, showing correlation coefficients >0.99. In addition, the developed method was used for the therapeutic drug monitoring of biperiden in real patient plasma.

Antitumor Effect of Traditional Drugs for Neurological Disorders: Preliminary Studies in Neural Tumor Cell Lines.

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood-brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood-brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood-brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it.

Metoclopramide induced acute dystonic reaction: A case report.

INTRODUCTION: and Importance: Metoclopramide is a frequently used anti-emetic medication for the treatment of vomiting secondary to medical conditions or chemotherapy. Metoclopramide is known to cause extrapyramidal symptoms (drug-induced movement disorder). While the dystonic reaction is an acute condition that may emerge after a single dose of metoclopramide, Tardive dyskinesia and Parkinsonism are generally seen after prolonged use. These reactions are more frequent in patients receiving high doses of metoclopramide especially in female patients, children, and older patients. CASE PRESENTATION: A 61-year-old male hypertensive patient was admitted into the internal medicine ward following persistent epigastric pain and vomiting. Initial laboratory and imaging assessments were insignificant, Upper GI endoscopy revealed features of gastritis. PPI and metoclopramide 10 mg 3 times daily were started. After 2 days, the patient developed an acute dystonic reaction. The drug was discontinued and anticholinergic biperiden was given. The dystonic reaction was controlled after the third dose. The patient was discharged following recovery. CONCLUSION: Metoclopramide can cause unpredictable acute dystonic reactions. This can be life-threatening and should be detected early. Extrapyramidal side effects should be monitored in patients on metoclopramide since a single dose can cause these symptoms. This case highlights an acute dystonic reaction following the administration of a metoclopromide injection. HIGHLIGHTS: A 61-year old man became sensitive to Metoclopromide administration. He developed an acute dystonic reaction following the administration of a metoclopromide injection. He was treated with biperiden 5 mg IV after the condition was diagnosed, and he responded well.

The antimuscarinic agent biperiden selectively impairs recognition of abstract figures without affecting the processing of non-words.

OBJECTIVES: The present study investigated the effects of biperiden, a muscarinic type 1 antagonist, on the recognition performance of pre-experimentally unfamiliar abstract figures and non-words in healthy young volunteers. The aim was to examine whether 4 mg biperiden could model the recognition memory impairment seen in healthy aging. METHODS: A double-blind, placebo-controlled, two-way crossover study was conducted. We used a three-phase (deep memorization, shallow memorization, and recognition) old/new discrimination paradigm in which memory strength was manipulated. Strong memories were induced by deep encoding and repetition. Deep encoding was encouraged by redrawing the abstract figures and mentioning existing rhyme words for the non-words (semantic processing). Weak memories were created by merely instructing the participants to study the stimuli (shallow memorization). RESULTS: Biperiden impaired recognition accuracy and prolonged reaction times of the drawn and the studied abstract figures. However, participants were biased towards "old" responses in the placebo condition. The recognition of the new abstract figures was unaffected by the drug. Biperiden did not affect the recognition of the non-words. CONCLUSIONS: Although biperiden may model age-related deficits in episodic memory, the current findings indicate that biperiden does not mimic age-related deficits in recognition performance.

Mutação missense de novo patogênica c. 2415C G (p. Asp805Glu) no gene ATP1A3 em paciente com hemiplegia alternante da infância com resposta favorável ao cloridrato de biperideno / A de novo missense pathogenic mutation c.2415C> G (p.Asp805Glu) in ATP1A3 gene in a patient with alternating hemiplegia of childhood with favorable response to biperiden hydrochloride

A Hemiplegia Alternante da Infância é um distúrbio neurológico grave e uma doença rara (1 em cada 100.000 recém-nascidos), caracterizado por ataques repetidos transitórios de hemiplegia episódica ou tetraplegia que podem durar minutos a horas, acompanhados por outros sintomas paroxísticos como anormalidades oculomotoras e autonômicas, distúrbios do movimento como ataxia, comprometimento cognitivo progressivo, convulsões, distonia e coreia. Os tratamentos atuais são amplamente sintomáticos. Neste relato de caso, apresentamos paciente do sexo feminino, 18 anos, na qual aos 10 meses apresentou o primeiro episódio aparente de crise convulsiva com versão ocular. O eletroencefalograma e tomografia computadorizada não revelaram anormalidades e foram administradas diversas medicações como fenobarbital, carbamazepina, valproato de sódio, topiramato, dicloridrato de flunarizina, clonazepam, cipro-heptadina e pizotifeno, todos sem resultado. Devidos aos sintomas extrapiramidais, paciente passou a utilizar biperideno, apresentando não só melhora da distonia, mas também no número de crises hemiplégicas. Aos 13 anos, ela foi diagnosticada com Hemiplegia Alternante da Infância na mutação patogênica missense de novo c.2415C G (p.Asp805Glu) no gene ATP1A3 apresentando boa resposta ao tratamento com cloridrato de biperideno. (AU)

Alternating hemiplegia of childhood is a severe neurological disorder and a rare disease (1 in 100,000 newborns), characterized by repeated transient attacks of episodic hemiplegia or tetraplegia that can last minutes to hours, accompanied by other paroxysmal symptoms such as oculomotor and autonomic abnormalities, movement disorders such as ataxia, progressive cognitive impairment, seizures, dystonia, and chorea. Current treatments are largely symptomatic. In this case report, we present a female patient, 18 years old, who presented the first apparent episode of seizure with ocular version at ten months of age. The electroencephalogram and CT scan revealed no abnormalities, and several medications such as phenobarbital, carbamazepine, sodium valproate, topiramate, flunarizine dihydrochloride, clonazepam, cyproheptadine and pizotifen were administered, all without result. Due to the extrapyramidal symptoms, the patient started using biperidene, showing improvement in dystonia and the number of hemiplegic seizures. At age 13, she was diagnosed with Alternating hemiplegia of Childhood in the pathogenic missense de novo mutation c.2415C>G (p.Asp805Glu) in the ATP1A3 gene showing a good response to treatment with biperidene hydrochloride. (AU)

Biperiden Challenge Model in Healthy Elderly as Proof-of-Pharmacology Tool: A Randomized, Placebo-Controlled Trial.

Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition-enhancing effects in early-phase clinical development in healthy subjects is difficult. A challenge with the M1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo-controlled, 3-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (-2.1 percentage point in adaptive tracking [95%CI, -3.043 to -1.148], verbal memory (2-3 fewer words recalled [95%CI, -5.9 to -0.2]) and working memory (up to a 50-millisecond increase in the n-back task reaction time [95%CI, 21.854-77.882]) compared with placebo. The PK data were best fitted by a 2-compartment model and showed high interoccasion and intersubject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction time, n-back accuracy, and adaptive tracking. In conclusion, biperiden caused M1 mAChR-related dose- and concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition-enhancing effects of new cholinergic compounds that are being developed.

Study on the interaction of three classical drugs used in psychiatry in albumin through spectrofluorimetric modeling.

Comparative study of haloperidol (HPD), biperiden (BPD) and clonazepam (CNZ) interactions with human and bovine serum albumin was performed based on fluorescence quenching analysis. We used mathematical modeling comparing spectrofluorimetric data to obtain information on the possibility of competition among three drugs by sites binding. Results showed that the three drugs studied have high affinity for albumin and suggest the existence of two site classes in HSA for HPD and only one class for BPD and CNZ, in the range of concentrations tested for each drug. Among them, only HPD forms complex with HSA. Comparing normalized quenching plots suggested that the primary sites in HSA and BSA for HPD and CNZ are located at subdomain IB, whereas BPD would bind in the subdomain IIA. Considering the competition for binding sites in HSA, titrations of HPD-HSA complex by BPD and CNZ, as well as the titration of HSA solution containing CNZ titrated by BPD, show that although the three drugs do not compete with each other for binding sites, their interaction with HSA can cause conformational change in the protein, and to increase or decrease the accessibility to binding sites for other drug. This may mean alteration in the free plasma drug concentrations.

Two decades of research towards a potential first anti-epileptic drug.

The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.

Metoclopramide-induced Acute Dystonia Misdiagnosed as an Epileptic Seizure in a Lupus Patient.

Acute dystonic reactions are the most prevalent extrapyramidal adverse effects associated with metoclopramide. It could be mistaken for a variety of other conditions, such as seizures, tetanus, and encephalitis, to name a few possibilities. We present a case of a 26-year-old female misdiagnosed as having an epileptic seizure who was rushed to the emergency unit with an involuntary bilateral upward deviation of the eyes, spasm, stiffness, lateral deviation of the neck, and protrusion of the tongue. Symptoms occurred 36 hours after the commencement of metoclopramide, used to treat nausea and vomiting in the referring hospital. All the laboratory work was normal. The drug was discontinued and 5 mg of intravenous biperiden was administered. The symptoms subsided in about 10 minutes with no recurrence. Metoclopramide-induced acute dystonia not only creates an anxious environment for patients but may also be life-threatening. Due to the high probability of misdiagnosis, detailed drug history and a high index of suspicion are critical in making the correct diagnosis.

Effects of biperiden (cholinergic muscarinic m1/m4 receptor antagonist) on ethanol conditioned place preference in mice.

BACKGROUND: Previous studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. AIMS: We examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. METHODS: Thirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. RESULTS: Biperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. CONCLUSIONS: Our results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.

Cholinergic and dopaminergic effects on prediction error and uncertainty responses during sensory associative learning.

Navigating the physical world requires learning probabilistic associations between sensory events and their change in time (volatility). Bayesian accounts of this learning process rest on hierarchical prediction errors (PEs) that are weighted by estimates of uncertainty (or its inverse, precision). In a previous fMRI study we found that low-level precision-weighted PEs about visual outcomes (that update beliefs about associations) activated the putative dopaminergic midbrain; by contrast, precision-weighted PEs about cue-outcome associations (that update beliefs about volatility) activated the cholinergic basal forebrain. These findings suggested selective dopaminergic and cholinergic influences on precision-weighted PEs at different hierarchical levels. Here, we tested this hypothesis, repeating our fMRI study under pharmacological manipulations in healthy participants. Specifically, we performed two pharmacological fMRI studies with a between-subject double-blind placebo-controlled design: study 1 used antagonists of dopaminergic (amisulpride) and muscarinic (biperiden) receptors, study 2 used enhancing drugs of dopaminergic (levodopa) and cholinergic (galantamine) modulation. Pooled across all pharmacological conditions of study 1 and study 2, respectively, we found that low-level precision-weighted PEs activated the midbrain and high-level precision-weighted PEs the basal forebrain as in our previous study. However, we found pharmacological effects on brain activity associated with these computational quantities only when splitting the precision-weighted PEs into their PE and precision components: in a brainstem region putatively containing cholinergic (pedunculopontine and laterodorsal tegmental) nuclei, biperiden (compared to placebo) enhanced low-level PE responses and attenuated high-level PE activity, while amisulpride reduced high-level PE responses. Additionally, in the putative dopaminergic midbrain, galantamine compared to placebo enhanced low-level PE responses (in a body-weight dependent manner) and amisulpride enhanced high-level precision activity. Task behaviour was not affected by any of the drugs. These results do not support our hypothesis of a clear-cut dichotomy between different hierarchical inference levels and neurotransmitter systems, but suggest a more complex interaction between these neuromodulatory systems and hierarchical Bayesian quantities. However, our present results may have been affected by confounds inherent to pharmacological fMRI. We discuss these confounds and outline improved experimental tests for the future.

Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer.

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.

Influence of muscarinic M1 receptor antagonism on brain choline levels and functional connectivity in medication-free subjects with psychosis: A placebo controlled, cross-over study.

An increasing number of studies implicate the muscarinic cholinergic system in cognitive dysfunction associated with psychosis. This study examined the effect of muscarinic M1 receptor modulation on anterior cingulate cortex (ACC) and striatal choline concentrations and the relation with cognitive performance, as well as functional connectivity of cognitive networks. Thirty medication-free subjects with a psychosis spectrum disorder and 30 gender, age and IQ-matched healthy control subjects underwent 1H-proton magnetic resonance spectroscopy (1H-MRS) twice, once after placebo and once after a single dose of biperiden (M1 receptor antagonist, 4 mg). A subset of 19 psychotic subjects and 28 controls underwent resting-state functional magnetic resonance imaging (rs-fMRI) as well. No significant differences were found in ACC and striatal choline levels, nor in functional connectivity, between the two groups after placebo. Moreover, M1 antagonism did not significantly affect choline levels or functional connectivity. No correlations were found between choline levels and cognition as well as psychotic symptoms. Our findings do not support an association between the cholinergic system and cognition and psychotic symptoms. However, the lack of group differences in choline concentrations and functional connectivity, both after biperiden and placebo, may indicate that there were no severe cholinergic abnormalities present in our sample.

The effects of the soluble guanylate cyclase stimulator riociguat on memory performance in healthy volunteers with a biperiden-induced memory impairment.

RATIONALE: After stimulation with nitric oxide, soluble guanylate cyclase (sGC) produces cyclic guanosine monophosphate (cGMP), which stimulates an important signalling pathway for long-term potentiation (LTP). By upregulating cGMP, LTP could be stimulated and thereby enhancing memory processes. The present study investigated the effects of the sGC stimulator riociguat on cognition in healthy volunteers. Participants were pre-treated with and without biperiden, which impairs memory performance, to investigate the memory-enhancing effects of riociguat. METHODS: Twenty volunteers participated in a double-blind placebo-controlled six-way crossover design with a cognitive test battery including the verbal learning task (VLT), n-back task, spatial memory test, the attention network test, and a reaction time task. Treatments were placebo and riociguat 0.5 mg, placebo and riociguat 1.0 mg, biperiden 2.0 mg and placebo, biperiden 2.0 mg and riociguat 0.5 mg and biperiden 2.0 mg and riociguat 1.0 mg. RESULTS: Blood pressure was found to be decreased and heart rate to be increased after administration of riociguat. Cognitive performance was not enhanced after administration of riociguat. Biperiden decreased episodic memory on the VLT, yet this deficit was not reversed by riociguat. CONCLUSION: This supports the notion that biperiden might be a valuable pharmacological model to induce episodic memory impairments as observed in AD/MCI.