Central Nervous System Activity Research Articles

Topographical distribution of the human brain to Plukenetia volubilis-based omega-3,6,9 enriched egg consumption

<span>Docosahexaenoic acid (DHA) is related to cognitive development. Consumers' brain health could benefit from changes in the omega 6:3 ratio. This study aimed to examine how the </span><em><span>Plukenetia volubilis</span></em><span>-based omega-3,6,9 enriched egg supplementation affects electrical brain activity during the attention/inhibition (Go/NoGo) test. Healthy subjects (n = 20) were chosen at random to eat 2 boiled </span><em><span>Plukenetia volubilis</span></em><span>-based omega-3,6,9 enriched eggs for 12 weeks. The ePrime v.3.0 application recorded behavioral performance during the Go/NoGo test during the electroencephalographic recording. The finding of this study was that twelve weeks of boiled </span><em><span>Plukenetia volubilis</span></em><span>-based omega-3,6,9 enriched egg consumption significantly decreased the reaction time responses compared to the baseline. The topographical distribution revealed that the mean amplitude of N1 produced a slightly larger amplitude in the 12<sup>th</sup> week compared to the baseline. The P3 component, following N1, was also larger in the 12<sup>th</sup> week compared to the baseline. After 12 weeks of consuming the </span><em><span>Plukenetia volubilis</span></em><span>-based omega-3,6,9 enriched eggs, the central nervous system activities during a Go/NoGo test were believed to be enhanced. </span>

Toward a biopsychosocial model of hoarding disorder

The present paper aims to elaborate on the original cognitive-behavioral model of hoarding disorder (HD; Frost & Hartl, 1996) by incorporating the results of recent research on biological and psychological contributors to HD. According to the proposed model, HD is characterized by several vulnerability factors that are thought to increase the likelihood that HD will develop, including genetic predisposition, abnormalities of brain structure, environmental factors such as traumatic life experiences, neuroticism, and impairments of cognitive function. Superimposed on these vulnerability factors is a biphasic abnormality of central and peripheral nervous system activity; at rest, or when doing completing symptom-irrelevant tasks, individuals with HD show blunted activity in brain regions that make up the salience network, including anterior cingulate cortex and insula. This blunted reactivity is further demonstrated through diminished error-related negativity (ERN) and decreased physiological arousal during error trials. However, when individuals with HD make decisions about possessions, they show relative hyperactivation of the salience network (and other brain regions), with accompanying indecisiveness, negative affect, exaggerated ERN, increased physiological arousal, and activation of maladaptive beliefs about, and attachment to, possessions. These factors lead to acquiring and saving behaviors, which are subsequently reinforced through emotion modification.

Abstract 10134: Role of Cardiac Sympathetic Nerves in Mediating the Central Nervous System Cardioprotective Effects of Leptin After Ischemia/Reperfusion Injury

We previously demonstrated that central nervous system (CNS) administration of leptin improves left ventricular (LV) function after myocardial infarction through mechanisms that are poorly understood. Increased cardiac sympathetic activity is an important compensatory mechanism to maintain cardiac output after ischemic injury, and previous studies showed that centrally-administered leptin increases sympathetic outflow to various tissues. In the present study, we tested the hypothesis that leptin’s CNS-mediated cardioprotective effects are mediated via cardiac sympathetic nerves. Male and female Wistar rats (~8 weeks of age) were submitted to cervical ganglia denervation (CGx) and instrumented with an intracerebroventricular (ICV) cannula in the brain lateral ventricle. After recovery and baseline assessment of cardiac function by echocardiography (ECHO) and an exercise performance test (Vmax), myocardial ischemia/reperfusion (I/R) was induced by temporary (60 min) ligation of the left anterior descending coronary artery. Vehicle (saline, 0.5 μL/hr) or leptin (0.62 μg/hr) was infused chronically for 28 days starting 20 min after reperfusion using osmotic pumps implanted subcutaneously in the scapular region and connected to the ICV cannula. Cardiac function was assessed weekly by ECHO. At the end of week 4, a final Vmax was performed and +dP/dt max was accessed by LV catheterization using a Millar catheter. Despite ~70% reduction in cardiac tyrosine hydroxylase positive fibers compared to sham, CGx did not prevent leptin’s CNS-mediated cardioprotective effects as indicated by improved ejection fraction (55±1 vs. 29±3 %), global longitudinal strain (-19±2 vs. -3±2 %), +dP/dt max (10214±614 vs. 7174±716 mmHg/s) and exercise performance (1.3±14 vs. -46.3±14 Δ% compared to baseline before I/R) when compared with CGx vehicle-treated animals. CGx also did not prevent the effect of ICV leptin to reduce septal collagen deposition and heart weight/tibia length post-I/R. These results suggests that leptin, via its CNS actions, improves cardiac function and remodeling after I/R injury independent of cardiac sympathetic innervation.

PSAT356 Propranolol Improves Bulbar Dysfunction Seen in Hyperthyroidism

Abstract Background Many symptoms of hyperthyroidism are mediated by the augmented activity of the adrenergic central nervous system. Rarely, symptoms of bulbar dysfunction are seen with thyrotoxicosis such as dysphagia and dysarthria. Beta blockers can abort or reduce these symptoms before anti-thyroid drugs are used. Case A 59-year-old woman with hypertension and gout, presented to the emergency department with poor oral intake and difficulties swallowing. Symptoms initially started as hoarseness of voice for 3 weeks then progressed to Globus sensation, difficulties swallowing and aspiration of solids and liquids. She also reported generalized muscle weakness, palpitations, increased sweating, tremors and 20 pounds weight loss in the preceding 2 months. Physical exam showed an ill-appearing, catechetic woman. Luedde exophthalmometry showed an absence of proptosis measuring 15 mm bilaterally without lid lag or stare and extraocular muscles were intact. The skin was silky without edema. The strength in the lower extremities was decreased and she was unable to squat or raise from a seated position. Labs showed creatinine of 2.7 mg/dL (0.4–1 mg/dL), BUN 49 (6–20 mg/dL), potassium of 3.1 (3.5–5.1 mmol/L), TSH < 0.02 (0.34–5.60 uIU/mL), FT4: 3.72. CT of the neck was obtained and multiple sub-centimetric hypodense thyroid nodules with calcifications were noted in the left thyroid lobe. Intravenous potassium chloride was given without improvement of dysphagia. 10 milligrams (mg) of propranolol were ordered to be given every 8 hours. After the first dose and over the next 24 hours she reported rapid improvement in dysphagia and muscle weakness. She was discharged on 15 mg of methimazole twice daily and propranolol 10 mg thrice daily. TSI and TRAB were elevated at 1.03 (normal < 0.54 IU/L) and 2.20 (normal<1.75 IU/L) respectively and the diagnosis of Graves’ disease was made. At her 3 weeks follow up, TSH was <0.02 (0.34–5.60 uIU/mL) with normal FT4. She reported complete resolution of dysphagia and improvement in lower extremities weakness. Discussion Hyperthyroidism may exert powerful effects on the neuro-muscular system. The pathogenesis of myopathy in hyperthyroidism is not fully understood. In hyperthyroid periodic paralysis, hypokalemia is present, and paresis is corrected with potassium supplementation. Our patient's symptoms did not improve with potassium supplement but dramatically improved after propranolol use and before the thyroid function was normalized. This implies a role of adrenergic overactivity in myopathy of hyperthyroidism. A study1 was conducted to quantify muscular weakness in hyperthyroidism and assess the response to therapy concluded that propranolol improves muscular weakness. Conclusion Prior to normalization of thyroid function, the use of beta blockers can alleviate symptoms of bulbar dysfunction. (1)Olson BR, Klein I, Benner R, Burdett R, Trzepacz P, Levey GS. Hyperthyroid myopathy and the response to treatment. Thyroid. 1991;1(2): 137-41. doi: 10.1089/thy.1991.1.137. PMID: 1688015. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia-Reperfusion: Roles of Sympathetic Innervation and Sex Differences.

Background Therapeutic strategies for preventing paradoxical reperfusion injury after myocardial ischemia are limited. We tested whether central nervous system actions of leptin induce important protective effects on cardiac function and metabolism after myocardial ischemia/reperfusion (I/R) injury, the role of cardiac sympathetic innervation in mediating these effects, and whether there are major sex differences in the cardioprotective effects of chronic central nervous system leptin infusion. Methods and Results Myocardial I/R was induced by temporary ligation of the left descending coronary artery in male and female Wistar rats instrumented with intracerebroventricular cannula in the lateral ventricle. Vehicle or leptin (0.62 μg/h) infusion was started immediately after reperfusion and continued for 28 days using osmotic minipumps connected to the intracerebroventricular cannula. Cardiac function was assessed by echocardiography, ventricular pressures, and exercise performance. Intracerebroventricular leptin treatment markedly attenuated cardiac dysfunction post-I/R as evidenced by improved ejection fraction (56.7±1.9 versus 22.6%±1.1%), maximal rate of left ventricle rise (11 680±2122 versus 5022±441 mm Hg) and exercise performance (-4.2±7.9 versus -68.2±3.8 Δ%) compared with vehicle-treated rats. Intracerebroventricular leptin infusion reduced infarct size in females, but not males, when compared with ad-lib fed or pair-fed saline-treated rats. Intracerebroventricular leptin treatment also increased cardiac NAD+/NADH content (≈10-fold) and improved mitochondrial function when compared with vehicle treatment. Cervical ganglia denervation did not attenuate the cardiac protective effects of leptin after I/R injury. Conclusions These data indicate that leptin, via its central nervous system actions, markedly improves overall heart function and mitochondrial metabolism after I/R injury regardless of sex, effects that are largely independent of cardiac sympathetic innervation.

Effects of visual stimulation using wooden-wall images with different amounts of knots on psychological and physiological responses

Wood is an important material used in decorating human living environment. Knots are prominent features found on wood surface. Moreover, they are commonly considered as undesirable surface defects, which reduce not only the mechanical properties but also the aesthetic qualities of lumber. The effects of visual stimulation using knotty wood on psychological responses among humans have been relatively well investigated. However, only few studies have assessed physiological responses. Hence, the present study aimed to assess whether knotty wood surface can reduce not only psychological but also physiological benefits for humans. Two full-sized knotty wooden-wall images and a clear wooden-wall image were used as visual stimuli using computer graphics techniques. Twenty-eight adult Japanese female university students viewed each image for 90 s in random order. During exposure to the visual stimuli, the oxyhemoglobin concentrations in the left and right prefrontal cortex and heart rate variability were consecutively measured and utilized as indicators of central and autonomic nervous system activities, respectively. In addition, the psychological effects of knotty images were examined using the modified semantic differential method and the Profile of Mood State 2nd Edition. There was no significant difference in the effects of the three images on physiological responses. All visual stimuli more or less promoted psychological comfort and relaxation. However, compared with the clear wooden-wall image, the wooden-wall image with several knots was associated with reduced psychological benefits, and the psychological responses in viewing the wooden-wall image with few knots did not remarkably differ.

177 (PB057) - BLU-945 or BLU-701 as single agents versus their combination with osimertinib in EGFR L858R driven tumor models

Background: The most common activating EGFR mutations (EGFRm) in non-small cell lung cancer (NSCLC) are exon 19 deletions (ex19del) and L858R substitutions. EGFR tyrosine kinase inhibitors (TKIs) as first-line (1L) therapy have improved outcomes in EGFR-driven advanced NSCLC; however, treatment resistance eventually occurs. Patients with EFGR L858R-driven advanced NSCLC (39% of all EGFR mutations in NSCLC) have shorter progression-free survival than those with EGFR ex19del, suggesting a significant unmet need. BLU-945 and BLU-701 are investigational, reversible, selective, orally available TKIs optimized for use as singleagent or combination therapy to suppress activating and on-target resistance EGFR mutants while sparing wild-type EGFR. in vivo studies have shown antitumor activity of BLU-945 against EGFR L858R, L858R/C797S, L858R/ T790M and EGFRm/T790M/C797S mutants, and BLU-701 against EGFRm and EGFRm/C797S mutants. Combination of BLU-945 and BLU-701 has also shown in vivo activity in EGFRm/C797S-driven mutant NSCLC. Combining BLU-945 or BLU-701 with osimertinib could potentially enable superior coverage of frequent on-target resistance mechanisms as well additional potency on the primary EGFR activating mutations. Central nervous system (CNS) metastases are an ongoing challenge in NSCLC. BLU-701 has already shown preclinical CNS activity; and both BLU-945 and BLU-701 are currently being investigated for potential treatment or prevention of CNS metastases. Due to poorer outcomes in patients with EGFR L858R-driven advanced NSCLC treated with osimertinib, and the inevitability of treatment resistance, studies were conducted to evaluate the activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging duration of response (DOR) in preclinical NSCLC tumor models driven by the L858R mutation. Material and Methods: The antitumor activity of BLU-945 or BLU-701, as single agents or in combination with osimertinib was evaluated in EGFR L858R-driven tumor models. Results: Administration of single-agent BLU-945 or BLU-701 resulted in tumor growth inhibition in EGFR L858R-driven PDX models. BLU-945 in combination with osimertinib resulted in prolonged DOR and survival when compared with BLU-945 or osimertinib as single agents. BLU-701 in combination with osimertinib resulted in superior tumor growth inhibition compared with BLU-701 or osimertinib as single agents. Conclusions: The in vivo antitumor activities of BLU-945 and BLU-701 as single agents suggest both BLU-945 and BLU-701 have the potential to be used as 1L therapy in patients with EGFR L858R-driven NSCLC. The superior in vivo antitumor activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging the DOR or increasing tumor growth inhibition in these models may have clinical application in improving outcomes of patients with EGFR L858R-driven NSCLC in 1L settings. Conflict of interest: Other Substantive Relationships: Tavera L, Dhande A, Dineen T, Iliou M, Rouskin-Faust T, Rozsahegyi E, Conti C: Employee and/or equity holder of Blueprint Medicines Corporation.

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?

In multiple sclerosis (MS) persisting disability can derive from acute relapses or, alternatively, from slow and steady deterioration, termed chronic progression. Emerging data suggest that the latter process occurs largely independent from relapse activity or development of new central nervous system (CNS) inflammatory lesions. Pathophysiologically, acute relapses develop as a consequence of de novo CNS infiltration of immune cells, while MS progression appears to be driven by a CNS-trapped inflammatory circuit between CNS-established hematopoietic cells as well as CNS-resident cells, such as microglia, astrocytes, and oligodendrocytes. Within the last decades, powerful therapies have been developed to control relapse activity in MS. All of these agents were primarily designed to systemically target the peripheral immune system and/or to prevent CNS infiltration of immune cells. Based on the above described dichotomy of MS pathophysiology, it is understandable that these agents only exert minor effects on progression and that novel targets within the CNS have to be utilized to control MS progression independent of relapse activity. In this regard, one promising strategy may be the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. In this review, we discuss where and to what extent BTK is involved in the immunological and molecular cascades driving MS progression. We furthermore summarize all mechanistic, preclinical, and clinical data on the various BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, orelabrutinib, BIIB091) that are currently in development for treatment of MS, with a particular focus on the potential ability of either drug to control MS progression.

Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain.

The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modification that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl− in the postsynaptic neuron. As the intracellular concentration increases, the inward flow of Cl− through an ionotropic GABA-A receptor is reduced, which decreases its hyperpolarizing (inhibitory) effect, a modulatory effect known as ionic plasticity. The loss of GABA-dependent inhibition enables a state of over-excitation within the spinal cord that fosters aberrant motor activity (spasticity) and chronic pain. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome. Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic benefits.

Microglial Responses and Pain Behaviors Are Exacerbated by Chronic Sleep Deprivation in Rats with Chronic Pain Via Neuroinflammatory Pathways

The inflammatory response of central nervous system (CNS) and microglial activation is important in the development of pain behaviors induced by sleep deprivation. We found that chronic sleep deprivation (CSD) aggravated pain behaviors in rats with chronic pain by upregulating expression of Toll-like receptor 4 (TLR4), NOD-like receptor pyrin domain containing 3 (NLRP3), and interleukin 1β (IL-1β), which promoted microglial activation in the brain. We also found that CSD increased numbers of Iba1+ and TLR4+ cells, as well as neuronal apoptosis. Inhibitors of TLR4 and NLRP3 (TAK-242 and MCC950, respectively) reduced expression levels of inflammatory factor proteins and M1-related factor mRNA, decreased microglial activation, and relieved the hyperalgesia caused by CSD. These results suggest that CSD aggravated pain behavior in rats with chronic pain through the TLR4/NLRP3/IL-1β signaling pathway, which mediates microglial activation and promotes CNS inflammation and neuronal apoptosis.

Pharmacological Actions of Valeriana Wallichii (Tagara): A Fundamental Analysis Supporting Traditional Benefits

Valeriana wallichii referred to as Indian Valeriana has a family circle Valerianaceae commonly known as "Tagara". India, Nepal, and China are home to the important variety of the Valeriana genus. It is indigenous to India and can be found between 8000-10000 feet altitudes in the Himalayan region. Valeriana is a popular ethnobotanical remedy throughout Europe for relieving stress and improving sleep. Vital Central nervous system (CNS) activity is mirrored in the genuine Ayurvedic text-based content and declared as one of the handiest treatments with inside the remedy of neurosis and is powerful in pacifying the body ache (Vedanasathpana), chills (Sheetprashmana), and headaches (Shirah shoolprshmana). Additionally, it has been addressed in the Charaka Samhita as a remedy for snake poisoning. The rhizome and supporting tissues of valerian are used to treat insomnia, epilepsy, hypertension, and psychosomatic disorders. Important phytochemicals can reduce pain, manage stress, protect the brain from radiation, and fight off microbes. Hesperidin, the statutory potent flavonoid, 6-methylapigenin, and four new varieties of the iridoids Valeriotetrates B and C, 8-methylvalepotriate, and 1,5-dihydroxy-3,8-epoxyvalechlorine A are just a few of the naturally occurring active phytochemicals in the Valeriana wallichii.

The Newborn's Reaction to Light as the Determinant of the Brain's Activation at Human Birth.

Developmental neuroscience research has not yet fully unveiled the dynamics involved in human birth. The trigger of the first breath, often assumed to be the marker of human life, has not been characterized nor has the process entailing brain modification and activation at birth been clarified yet. To date, few researchers only have investigated the impact of the extrauterine environment, with its strong stimuli, on birth. This ‘hypothesis and theory' article assumes the role of a specific stimulus activating the central nervous system (CNS) at human birth. This stimulus must have specific features though, such as novelty, efficacy, ubiquity, and immediacy. We propose light as a robust candidate for the CNS activation via the retina. Available data on fetal and neonatal neurodevelopment, in particular with reference to retinal light-responsive pathways, will be examined together with the GABA functional switch, and the subplate disappearance, which, at an experimental level, differentiate the neonatal brain from the fetal brain. In this study, we assume how a very rapid activation of retinal photoreceptors at birth initiates a sudden brain shift from the prenatal pattern of functions to the neonatal setup. Our assumption implies the presence of a photoreceptor capable of capturing and transducing light/photon stimulus, transforming it into an effective signal for the activation of new brain functions at birth. Opsin photoreception or, more specifically, melanopsin-dependent photoreception, which is provided by intrinsically photosensitive retinal ganglion cells (ipRGCs), is considered as a valid candidate. Although what is assumed herein cannot be verified in humans based on knowledge available so far, proposing an important and novel function can trigger a broad range of diversified research in different domains, from neurophysiology to neurology and psychiatry.

Investigation of Dopamine Release on Self-assembled Monolayers by Scanning Electrochemical Microscopy

Dopamine, a neurotransmitter, controls many psychological and behavioral activities of the mammalian central nervous system. Over secretion of dopamine can make the body overexcited and lead to mental disorders. Whereas, less secretion can develop Parkinson’s symptoms. Therefore, achieving controlled release of dopamine plays a vital role in life sciences. In this work, two kinds of self-assembled monolayers were prepared by non-covalent and covalent assembly, respectively, to reach the function of dopamine controllable release. After characterization of the two self-assembled monolayers, the release function was well monitored and analyzed by scanning electrochemical microscopy. The result showed that ion pair effect, as well as acids and alkali, would stimulate a steady-state release of dopamine on the non-covalent monolayers. The combined effect of alkali and positive potential would stimulate a steady-state release of dopamine on the covalent monolayers. This work successfully reaches the controllable release of dopamine in vitro, and offers some reference value for this function in vivo.

Current perspectives on benzoflavone analogues with potent biological activities: A review

Medicinal chemistry investigators have isolated and synthesized benzoflavone analogues with diverse bioactivities including enzyme inhibitory activity, central nervous system (CNS) activity, anti-inflammatory activity, anti-microorganism activity, hypoglycemic activity, and receptor modulating potential. SAR (Structure-Activity Relationship) studies have been conducted extensively and plenty of benzoflavone analogues have been prepared for potential targets. Herein, we review the pharmacology properties and SAR for benzoflavone analogues, and provide a brief summarization of synthetic strategies, wishing to give perspective on the research and development of benzoflavone derivatives.

EP08.02-071 Brain Metastases in EGFR-mutant NSCLC: Outcome of Osimertinib +/- Radiation Therapy in a Real-World Canadian Cohort

Intracranial metastasis is a significant complication in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib is an oral tyrosine kinase inhibitor which has central nervous system (CNS) activity. However, many patients with intracranial metastases are treated with cranial radiation therapy (RT), which can have considerable toxicities. The optimal treatment for this patient population has not been elucidated. The purpose of this study was to assess CNS outcomes of real-world patients treated with Osimertinib +/- RT.

EP02.04-003 A Retrospective Comparison of Survival Outcomes in EGFR-mutated, NSCLC Patients on Osimertinib +/- Brain Metastases

Intracranial disease progression is a significant complication in patients with EGFR-positive non-small cell lung cancer (NSCLC) that can impact performance status, quality of life, and treatment options for patients. There is an increased need of oral tyrosine kinase inhibitors with central nervous system (CNS) activity in treating this population to prolong survival. Osimertinib is an oral tyrosine kinase inhibitor (TKI) which has demonstrated penetration of the blood brain barrier and effective treatment of intracranial metastases in some patients.

EP08.02-018 Phase 1/2 Study of BLU-451, a Small Molecule Inhibitor of EGFR, in EGFR Exon 20 Insertion-Mutant Incurable Advanced Cancers

Oncogenic EGFR exon 20 insertion (ex20ins) mutations, found in ∼2% of non-small cell lung cancers (NSCLC) and a small percentage of other cancers, are generally not responsive to EGFR-targeted agents that have been approved for treatment of NSCLC with a common EGFR mutation, including L858R and exon 19 deletion. Similar to these more common types of EGFR-mutated NSCLC, central nervous system (CNS) metastases are a challenge with EGFR ex20ins mutant NSCLC and are associated with poor outcomes. While two EGFR ex20ins-targeting drugs were recently approved by the US Food and Drug Administration (amivantamab and mobocertinib), neither have established CNS activity.

Disease correction in mucopolysaccharidosis type IIIB mice by intraparenchymal or cisternal delivery of a capsid modified AAV8 codon-optimized NAGLU vector.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood-brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.

China versus the world: Impact of international drug policy on postmortem stimulant detections in England, Wales and Northern Ireland

To highlight trends in postmortem detections of stimulants in England, Wales and Northern Ireland (2006–2020) and their correlation with UK, Chinese, and UN drug controls. Stimulant drugs increase central nervous system activity, and are used recreationally for their pleasurable and invigorating effects. The number of recreational stimulants available on the illicit drug market was considerably broadened in the mid-2000s by the introduction of novel stimulants within the wave of novel psychoactive substances (NPS), often purported to originate from China. The UK Government sought to reduce NPS use to curb their associated harms and mortality, and consequentially introduced a series of specific and generic controls within the 1971 Misuse of Drugs Act (MDA), followed by the 2016 Psychoactive Substances Act, which automatically bans all NPS not controlled under the MDA. Concurrently and since, the UN Commission on Narcotic Drugs (UNCND) and the Council of China have also banned various NPS: 7 stimulant NPS were added to the International Drug Control Conventions by UNCND, to which China is a signatory, between 2015 and 2021, with the Council of China banning a further 81 stimulant NPS within the same time frame. This study aims to evaluate how deaths following stimulant use in England, Wales and Northern Ireland have evolved over time, considering the introduction of UK, Chinese and UN prohibitive drug controls. The National Programme on Substance Abuse Deaths has collected data on deaths following psychoactive drug use from coroners across England, Wales and Northern Ireland since 1997. Basic decedent demographics are reported (e.g., age, gender) along with details pertaining to their death (e.g., cause of death, drugs detected at postmortem). Cases with stimulants detected at postmortem that occurred 2006–2020 were extracted on November 1st 2021 and analysed. The King's College London Biomedical and Health Sciences, Dentistry, Medicine and Natural and Mathematical Sciences Research Ethics Sub-Committee (BDM RESC) confirmed in November 2020 that NPSAD does not require BDM RESC review as all subjects are deceased. In 2006–2008 cocaine, amphetamine and MDMA comprised the majority (95%, n = 1651/1738) of postmortem stimulant detections. This fell to below 75% in 2010 ( n = 316/422) due to detections of stimulant NPS (25%, n = 106/422), before rising again to above 90% in 2016 ( n = 798/834). Cocaine detections are currently at an all-time high, having steadily increased from 233 detections in 2010 to 1094 in 2020 – an increase of 470%. Forty-five different stimulant NPS were detected in deaths reported to the NPSAD, and accounted for a total of 1242 detections. Where stimulant NPS were first controlled by UK drug legislation there is, in some instances, a clear effect in reducing detections (e.g., benzylpiperazine detections pre-UK control n = 54, post-UK control n = 11), but in others there was no clear effect (e.g., methylone detections pre-UK control n = 2, post-UK control n = 19). Similarly, when controlled in China, either through the Council of China or the UNCND, there were reductions in detections for some stimulant NPS (e.g., MDPHP detections pre-Chinese control n = 26, post-Chinese control n = 4), but not others (e.g., dibutylone detections pre-Chinese control n = 1, post-Chinese control n = 7). UK and Chinese prohibitive drug policies have had clear effects on overall stimulant NPS postmortem detection trends. The number of deaths following cocaine use has dramatically increased in recent years as the drug has become both cheaper and purer, further cementing the UK's reputation as the ‘cocaine capital of Europe’. Following their control stimulant NPS have fallen out of favour, with users turning or returning to use of classical stimulants, particularly cocaine. Urgent action is needed to address the ever-increasing mortality trend following cocaine use.

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.

Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH-MAGL inhibition properties. Phenyl [4-(piperidin-1-ylmethyl)phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC50 = 19 nM), benzyl (1H-benzo[d]imidazol-2-yl)carbamate (3h) was the most potent FAAH inhibitor (IC50 = 55 nM), and phenyl (6-fluorobenzo[d]thiazol-2-yl)carbamate (2i) egressed as a nonselective dual FAAH-MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent-reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood-brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug-likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.