Investigating Real-World Benztropine Usage Patterns in Movement Disorders: Claims Analysis and Health Care Provider Survey Results.

Objective: To evaluate real-world treatment patterns for patients initiating benztropine and to understand treatment approaches in patients with drug-induced movement disorders from a health care provider perspective.Methods: A retrospective claims analysis was conducted among patients with evidence of benztropine initiation from January 2017 through March 2020 to assess treatment patterns and patient health care resource utilization. Subsequently, a 30-minute, United States-based online survey fielded from December 2021 to January 2022 was sent to physicians, nurse practitioners, and physician assistants who reported a primary care or psychiatry specialty currently treating drug-induced movement disorders and prescribed benztropine.Results: The health care claims analysis included 112,542 patients. Polypharmacy and multiple comorbidities were frequent characteristics in this population; 54.1% of patients had ≥ 2 comorbidities at baseline, and 59.1% had claims for > 10 medications. Benztropine was used for > 3 months in > 50% of the population. Health care costs and resource utilization were high, with mean all-cause pharmacy and outpatient costs totaling $11,755. Survey results from 349 primary care or psychiatry health care providers indicated that benztropine is often used in non-tardive dyskinesia drug-induced movement disorders but frequently continued for > 3 months or used in tardive dyskinesia. In this study, psychiatry providers prescribed benztropine in line with guideline recommendations more often than primary care providers; however, < 40% indicated familiarity with 2020 American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia.Conclusions: These complementary analyses suggest that benztropine is used long-term in non-tardive dyskinesia drug-induced movement disorders and in tardive dyskinesia despite risks of worsening tardive dyskinesia or adverse effects.Prim Care Companion CNS Disord 2023;25(4):22m03472. Author affiliations are listed at the end of this article.

Withdrawal-Emergent Dyskinesia Related to Benztropine: A Case Report.

INTRODUCTION: Benztropine is an anticholinergic drug used as a therapy for Parkinson's disease and treatment for extrapyramidal side effects. While tardive dyskinesia is an involuntary movement disorder that often occurs gradually after long-term use of medications, it does not commonly present acutely. CASE PRESENTATION: A 31-year-old White woman experiencing psychosis presented with spontaneous, acute-onset dyskinesia induced with the withdrawal of benztropine. She had been followed in our academic outpatient clinic for medication management and intermittent psychotherapy. DISCUSSION: The pathophysiology of tardive dyskinesia is not fully understood, but several hypotheses exist, including the involvement of changes in basal ganglia neuronal systems. To our knowledge, this is the first case report to document acute-onset dyskinesia associated with the withdrawal of benztropine. CONCLUSION: his case report, which describes an atypical response to discontinuing benztropine, might offer the scientific community potential clues to better understand the pathophysiology of tardive dyskinesia.

Benztropine and suicide attempts and intentional self-harm.

BACKGROUND: This large-scale pharmacoepidemiologic study was conducted to confirm a previous signal for decreased risk of suicide attempt following prescription fills for benztropine. METHODS: We used a within-person exposure-only cohort design to study the dynamic association between benztropine prescription fills over a 12-month period and suicidal events (suicide attempts and intentional self-harm) in 62,493 patients with private health insurance (MarketScan - MS) who filled a new benztropine prescription between 2011 and 2019. A discrete-time survival analysis was used to analyze the data, adjusting for age, sex, diagnoses related to suicidal behavior, Parkinson's disease, medical comorbidities, history of suicide attempts, concomitant CNS medications, and time-varying antipsychotic use. RESULTS: Overall, there were 486 suicidal events (0.8%) following the index end-date of the one-year baseline period. Benztropine use was associated with fewer suicidal events (HR=0.63, 95% CI = 0.50, 0.80). Patients treated with antipsychotics and benztropine had a similar reduction in suicidal events as patients treated with benztropine alone in both within-subject and between-subject analyses. Similar associations were found for patients with bipolar disorder or schizophrenia, and those treated with newer versus older generation antipsychotics. Dose-response and duration response relationships were found, with an overall 6% reduction in suicidal events per 1 mg equivalent dosage per month, that was similar in those treated and those not treated with antipsychotics. INTERPRETATIONS: Benztropine was found to lower suicidal event rates, comparably in those receiving or not receiving antipsychotic medications, regardless of the presence of major psychiatric disorders. This observation warrants testing in a randomized clinical trial. FUNDING: No funding sources were utilized for this manuscript.

FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder.

Post-traumatic stress disorder (PTSD) leads to enhanced alcohol drinking and development of alcohol use disorder (AUD). Identifying shared neural mechanisms might help discover new therapies for PTSD/AUD. Here, we employed a rat model of comorbid PTSD/AUD to evaluate compounds that inhibit FK506-binding protein 51 (FKBP5), a co-chaperone modulator of glucocorticoid receptors implicated in stress-related disorders. Male and female rats received a familiar avoidance-based shock stress followed by voluntary alcohol drinking. We then assessed trauma-related behaviors through sleep bout cycles, hyperarousal, fear overgeneralization, and irritability. To evaluate the role of stress and alcohol history on the sensitivity to FKBP5 inhibitors, in two separate studies, we administered two FKBP5 inhibitors, benztropine (Study 1) or SAFit2 (Study 2). FKBP5 inhibitors were administered on the last alcohol drinking session and prior to each trauma-related behavioral assessment. We also measured plasma corticosterone to assess the actions of FKBP5 inhibitors after familiar shock stress and alcohol drinking. Benztropine reduced alcohol preference in stressed males and females, while aggressive bouts were reduced in benztropine-treated stressed females. During hyperarousal, benztropine reduced several startle response outcomes across stressed males and females. Corticosterone was reduced in benztropine-treated stressed males. The selective FKBP5 inhibitor, SAFit2, reduced alcohol drinking in stressed males but not females, with no differences in irritability. Importantly, SAFit2 decreased fear overgeneralization in stressed males and females. SAFit2 also reduced corticosterone across stressed males and females. Neither FKBP5 inhibitor changed sleep bout structure. These findings indicate that FKBP5 inhibitors modulate stress-related alcohol drinking and partially modulate trauma-related behaviors. This work supports the hypothesis that targeting FKBP5 may alleviate PTSD/AUD comorbidity.

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action.

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.

Blockade of Voltage-Dependent K+ Channels by Benztropine, a Muscarinic Acetylcholine Receptor Inhibitor, in Coronary Arterial Smooth Muscle Cells.

We investigated the effect of the acetylcholine muscarinic receptor inhibitor benztropine on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Benztropine inhibited Kv currents in a concentration-dependent manner, with an apparent IC50 value of 6.11 ± 0.80 µM and Hill coefficient of 0.62 ± 0.03. Benztropine shifted the steady-state activation curves toward a more positive potential, and the steady-state inactivation curves toward a more negative potential, suggesting that benztropine inhibited Kv channels by affecting the channel voltage sensor. Train pulse (1 or 2 Hz)-induced Kv currents were effectively reduced by the benztropine treatment. Furthermore, recovery time constants of Kv current inactivation increased significantly in response to benztropine. These results suggest that benztropine inhibited vascular Kv channels in a use (state)-dependent manner. The inhibitory effect of benztropine was canceled by pretreatment with the Kv 1.5 inhibitor, but there was no obvious change after pretreatment with Kv 2.1 or Kv7 inhibitors. In conclusion, benztropine inhibited the Kv current in a concentration- and use (state)-dependent manner. Inhibition of the Kv channels by benztropine primarily involved the Kv1.5 subtype. Restrictions are required when using benztropine to patients with vascular disease.

Amisulpride withdrawal akathisia responding to aripiprazole with propranolol in first-onset psychosis: a case report.

BACKGROUND: Akathisia tends to develop as an early complication of antipsychotic treatment in a dose-dependent manner. Although withdrawal akathisia has been reported after the discontinuation or dose reduction of typical antipsychotic drugs, akathisia following atypical antipsychotic drug withdrawal remains a rare phenomenon. CASE PRESENTATION: A 24-year-old woman with an acute psychotic episode was admitted and initially treated with aripiprazole. The aripiprazole dose was titrated up to 30 mg/day over 9 days and maintained for the next 3 days; however, her psychotic symptoms persisted without change. She was switched to amisulpride, with the dose increased over 2 weeks to 1000 mg/day. Subsequently, although the patient's psychotic episode subsided, her serum prolactin levels increased markedly. After discharge, the amisulpride dose was increased to 1200 mg/day owing to auditory hallucinations and was maintained with quetiapine (100-200 mg/day) and benztropine (1 mg/day) for 13 weeks. Given the potential for hyperprolactinemia as a side effect, the amisulpride dose was reduced to 800 mg/day concurrently with the discontinuation of benztropine; however, these changes resulted in severe restlessness without other extrapyramidal symptoms. The withdrawal akathisia disappeared over 2 weeks after switching to aripiprazole (10 mg/day) with propranolol (40 mg/day) and the patient's prolactin levels had normalized after 6 months of aripiprazole monotherapy. CONCLUSIONS: The present case highlights the potential for the development of withdrawal akathisia when the dose of amisulpride is tapered abruptly. Thus, a slow tapering and careful monitoring are recommended when switching from amisulpride to other antipsychotic drugs. Furthermore, this case suggests that changing the regimen to aripiprazole with propranolol may be a potential option for amisulpride withdrawal akathisia superimposed on pre-existing hyperprolactinemia.

Unprovoked Dystonic Reaction in a Child Taking Long-Term Methylphenidate.

In this report, we discuss the case of a 9-year-old male with Attention Deficit Hyperactivity Disorder (ADHD) on long-term methylphenidate and guanfacine who experienced acute orofacial dystonia that resolved immediately with the administration of benztropine. Current literature describes various cases of methylphenidate-induced dystonia, but ours appears to be the first reported instance of spontaneous dystonia without a recent change in dose or medication change. This may suggest the possibility of methylphenidate-induced dystonia spontaneously occurring several years after initiation.

Effect of low-dose amitriptyline on reducing pain in clinical knee osteoarthritis compared to benztropine: study protocol of a randomised, double blind, placebo-controlled trial.

BACKGROUND: Knee osteoarthritis is a major cause of pain and disability. Pain control is poor, with most patients remaining in moderate to severe pain. This may be because central causes of pain, a common contributor to knee pain, are not affected by current treatment strategies. Antidepressants, such as amitriptyline, have been used to treat chronic pain in other conditions. The aim of this randomised, double blind, controlled trial, is to determine whether low dose amitriptyline reduces pain in people with painful knee osteoarthritis over 3 months compared to benztropine, an active placebo. METHODS/DESIGN: One hundred and sixty people with painful radiographic knee osteoarthritis will be recruited via clinicians, local and social media advertising. Participants will be randomly allocated in a 1:1 ratio to receive either low dose amitriptyline (25 mg) or active placebo (benztropine mesylate, 1 mg) for 3 months. The primary outcome is change from baseline in knee pain (WOMAC pain subscale) at 12 weeks. Secondary outcomes include change in function (total WOMAC) and the proportion of individuals achieving a substantial response (≥ 50% reduction in pain intensity, measured by Visual Analog Scale, VAS, from no pain to worst pain imaginable, 0-100 mm) and moderate response (≥ 30% reduction in pain intensity, measured by VAS) at 12 weeks. Intention to treat analyses will be performed. Subgroup analyses will be done. DISCUSSION: This study will provide high level evidence regarding the effectiveness of low dose amitriptyline compared to benztropine in reducing pain and improving function in knee OA. This trial has the potential to provide an effective new therapeutic approach for pain management in knee osteoarthritis, with the potential of ready translation into clinical practice, as it is repurposing an old drug, which is familiar to clinicians and with a well described safety record. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry prior to recruitment commencing ( ACTRN12615000301561 , March 31, 2015, amended 14 December 2018, February 2021). Additional amendment requested 18 July 2021.

Human embryonic stem cell-derived cardiomyocyte platform screens inhibitors of SARS-CoV-2 infection.

Patients with cardiovascular comorbidities are more susceptible to severe infection with SARS-CoV-2, known to directly cause pathological damage to cardiovascular tissue. We outline a screening platform using human embryonic stem cell-derived cardiomyocytes, confirmed to express the protein machinery critical for SARS-CoV-2 infection, and a SARS-CoV-2 spike-pseudotyped virus system. The method has allowed us to identify benztropine and DX600 as novel inhibitors of SARS-CoV-2 infection in a clinically relevant stem cell-derived cardiomyocyte line. Discovery of new medicines will be critical for protecting the heart in patients with SARS-CoV-2, and for individuals where vaccination is contraindicated.

Effects of benztropine analogs on delay discounting in rats.

RATIONALE: Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability. OBJECTIVES: The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD. METHODS: Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control. RESULTS: d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding. CONCLUSIONS: AHN 1-055 may be of clinical utility in the treatment of ADHD.

Risperidone-Induced Acute Laryngeal Dystonia: A Case Report.

BACKGROUND Antipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms. Acute laryngeal dystonia (ALD) is a rare and lethal form of extrapyramidal reaction. CASE REPORT A 27-year-old woman with schizophrenia on risperidone presented to our Emergency Department with a sensation of choking and respiratory distress, mimicking a panic attack. She developed a generalized dystonic reaction in the hospital, leading to diagnosis risperidone-associated ALD as a cause of her initial problems. She was discharged with an emphasis on being compliant with anticholinergic medication. However, her persistent respiratory symptoms prompted us to revisit the management plan. Her risperidone dose was tapered down to discontinue and an alternate drug was chosen. CONCLUSIONS ALD must be considered as a differential diagnosis when patients on antipsychotic medications present with respiratory distress. Our case highlights the association of ALD with an atypical antipsychotic agent, risperidone. Prompt recognition of this entity is necessary to prevent complications and guide definitive management.

Psychotropics in Your Medicine Cabinet: A Case Study of Dimenhydrinate Use.

: Reporting of intoxication and withdrawal from aberrant use of over-the-counter medication has been sparse and inconsistent in literature. Attributed to their anticholinergic properties, medications such as dimenhydrinate (Gravol) taken in supratherapeutic doses have been associated with euphoria, anxiolysis, and hallucinations. We present a case of a woman in her forties, with a psychiatric history of bipolar disorder, and complex concurrent medical history including familial Mediterranean fever (FMF), and fibromyalgia, admitted for withdrawal management of her intravenous dimenhydrinate use. As a result of her FMF, there were numerous hospital admissions and treatment which required intravenous access. Hence, a physician-inserted intravenous access port was placed on her chest. The port was maintained monthly with the help of a community agency. In this port, she was injecting 100 to 200 mg of dimenhydrinate hourly for its euphoric and calming effects, consuming upwards of 2400 mg/d. Comprehensive laboratory work-up and urine drug screening were unremarkable. Vital signs were stable. Her mental status at time of admission was lethargic, unfocused, but calm. Her withdrawal symptoms included severe nausea, vomiting, sedation, headaches, dizziness, anxiety, and muscle stiffness. Her detoxification was managed with benztropine and lorazepam, and was well tolerated. The patient was discharged to a community inpatient rehabilitation center. Urine drug testing before discharge was negative. This case draws attention to the addictive potential of dimenhydrinate and offers a regime for its medical withdrawal management. Additionally, this case highlights that screening and management of over-the-counter medications warrants further clinical consideration and investigation.

Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth.

The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. We have evaluated whether benztropine can increase anti-tumoral efficacy of oxaliplatin, while preventing its neurotoxicity.We showed that benztropine improves acute and chronic clinical symptoms of oxaliplatin-induced peripheral neuropathies in mice. Sensory alterations detected by electrophysiology in oxaliplatin-treated mice were consistent with a decreased nerve conduction velocity and membrane hyperexcitability due to alterations in the density and/or functioning of both sodium and potassium channels, confirmed by action potential analysis from ex-vivo cultures of mouse dorsal root ganglion sensory neurons using whole-cell patch-clamp. These alterations were all prevented by benztropine. In oxaliplatin-treated mice, MBP expression, confocal and electronic microscopy of the sciatic nerves revealed a demyelination and confirmed the alteration of the myelinated axons morphology when compared to animals injected with oxaliplatin plus benztropine. Benztropine also prevented the decrease in neuronal density in the paws of mice injected with oxaliplatin. The neuroprotection conferred by benztropine against chemotherapeutic drugs was associated with a lower expression of inflammatory cytokines and extended to diabetic-induced peripheral neuropathy in mice.Mice receiving benztropine alone presented a lower tumor growth when compared to untreated animals and synergized the anti-tumoral effect of oxaliplatin, a phenomenon explained at least in part by benztropine-induced ROS imbalance in tumor cells.This report shows that blocking muscarinic receptors with benztropine prevents peripheral neuropathies and increases the therapeutic index of oxaliplatin. These results can be rapidly transposable to patients as benztropine is currently indicated in Parkinson's disease in the United States.

Identification of the benztropine analog [125I]GA II 34 binding site on the human dopamine transporter.

The dopamine transporter (DAT) is a neuronal membrane protein that is responsible for reuptake of dopamine (DA) from the synapse and functions as a major determinant in control of DA neurotransmission. Cocaine and many psychostimulant drugs bind to DAT and block reuptake, inducing DA overflow that forms the neurochemical basis for euphoria and addiction. Paradoxically, however, some ligands such as benztropine (BZT) bind to DAT and inhibit reuptake but do not produce these effects, and it has been hypothesized that differential mechanisms of binding may stabilize specific transporter conformations that affect downstream neurochemical or behavioral outcomes. To investigate the binding mechanisms of BZT on DAT we used the photoaffinity BZT analog [125I]N-[n-butyl-4-(4‴-azido-3‴-iodophenyl)]-4',4″-difluoro-3α-(diphenylmethoxy)tropane ([125I]GA II 34) to identify the site of cross-linking and predict the binding pose relative to that of previously-examined cocaine photoaffinity analogs. Biochemical findings show that adduction of [125I]GA II 34 occurs at residues Asp79 or Leu80 in TM1, with molecular modeling supporting adduction to Leu80 and a pharmacophore pose in the central S1 site similar to that of cocaine and cocaine analogs. Substituted cysteine accessibility method protection analyses verified these findings, but identified some differences in structural stabilization relative to cocaine that may relate to BZT neurochemical outcomes.

Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models.

Development of Biomarkers for Inhibition of SLC6A19 (B°AT1)-A Potential Target to Treat Metabolic Disorders.

Recent studies have established that dietary protein restriction improves metabolic health and glucose homeostasis. SLC6A19 (B°AT1) is the major neutral amino acid transporter in the intestine and carries out the bulk of amino acid absorption from the diet. Mice lacking SLC6A19 show signs of protein restriction, have improved glucose tolerance, and are protected from diet-induced obesity. Pharmacological blockage of this transporter could be used to induce protein restriction and to treat metabolic diseases such as type 2 diabetes. A few novel inhibitors of SLC6A19 have recently been identified using in vitro compound screening, but it remains unclear whether these compounds block the transporter in vivo. To evaluate the efficacy of SLC6A19 inhibitors biomarkers are required that can reliably detect successful inhibition of the transporter in mice. A gas chromatography mass spectrometry (GC-MS)-based untargeted metabolomics approach was used to discriminate global metabolite profiles in plasma, urine and faecal samples from SLC6A19ko and wt mice. Due to inefficient absorption in the intestine and lack of reabsorption in the kidney, significantly elevated amino acids levels were observed in urine and faecal samples. By contrast, a few neutral amino acids were reduced in the plasma of male SLC6A19ko mice as compared to other biological samples. Metabolites of bacterial protein fermentation such as p-cresol glucuronide and 3-indole-propionic acid were more abundant in SLC6A19ko mice, indicating protein malabsorption of dietary amino acids. Consistently, plasma appearance rates of [14C]-labelled neutral amino acids were delayed in SLC6A19ko mice as compared to wt after intra-gastric administration of a mixture of amino acids. Receiver operating characteristic (ROC) curve analysis was used to validate the potential use of these metabolites as biomarkers. These findings provide putative metabolite biomarkers that can be used to detect protein malabsorption and the inhibition of this transporter in intestine and kidney.

Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD.

Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.