Central Nervous System Activity Research Articles

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.

Pharmacotherapeutics of aprepitant and pregabalin in neuropathic pain and refractory pruritus in a patient diagnosed with a cutaneous T-cell lymphoma

Background/Aims Palliative care nurse specialists are required to have a high level of knowledge and expertise in the management of complex symptoms. As a result of patient complexity, clinicians are often faced with advising on multiple drug regimes. This often requires clinical nurse specialists to have knowledge of pharmacotherapeutics to ensure safe and rational prescribing. In the form of a case study, the author has critically discussed the use of aprepitant and pregabalin in the management of neuropathic pain and refractory pruritus in a patient diagnosed with a cutaneous T cell lymphoma. These drugs are not routinely prescribed together and therefore the author has explored potential pharmacokinetic interactions. Case presentation The case presented a 49-year-old lady with an advanced metastatic cutaneous T-cell lymphoma with failed remission despite extensive oncological treatment. She was referrd to the to hospital specialist palliative care team for treatment of refractory pruritus and neuropathic pain. Conclusion Aprepitant is considered an effective anti-pruritic agent that is normally well tolerated; however, careful consideration must be taken because of extensive drug interactions. Caution is also required in patients with hepatic impairment. Pregabalin is often used in specialist palliative care for the management of neuropathic pain because of its efficacy and ease of titration. Caution must be taken in prescribing in patients with renal impairment. As pregabalin is not bound to plasma proteins nor metabolised by the liver, the risk of pharmacokinetic interaction with aprepitant is minimal. As both drugs cross the blood brain-barrier, clinicians must monitor for adverse central nervous system activity. This case study highlights the importance of pharmacotherapeutics in ensuring safe and rational prescribing, with the need to continue to integrate this knowledge into future practice as nurse prescribers.

Pairwise and higher-order measures of brain-heart interactions in children with temporal lobe epilepsy

Objective. While it is well-known that epilepsy has a clear impact on the activity of both the central nervous system (CNS) and the autonomic nervous system (ANS), its role on the complex interplay between CNS and ANS has not been fully elucidated yet. In this work, pairwise and higher-order predictability measures based on the concepts of Granger Causality (GC) and partial information decomposition (PID) were applied on time series of electroencephalographic (EEG) brain wave amplitude and heart rate variability (HRV) in order to investigate directed brain-heart interactions associated with the occurrence of focal epilepsy. Approach. HRV and the envelopes of δ and α EEG activity recorded from ipsilateral (ipsi-EEG) and contralateral (contra-EEG) scalp regions were analyzed in 18 children suffering from temporal lobe epilepsy monitored during pre-ictal, ictal and post-ictal periods. After linear parametric model identification, we compared pairwise GC measures computed between HRV and a single EEG component with PID measures quantifying the unique, redundant and synergistic information transferred from ipsi-EEG and contra-EEG to HRV. Main results. The analysis of GC revealed a dominance of the information transfer from EEG to HRV and negligible transfer from HRV to EEG, suggesting that CNS activities drive the ANS modulation of the heart rhythm, but did not evidence clear differences between δ and α rhythms, ipsi-EEG and contra-EEG, or pre- and post-ictal periods. On the contrary, PID revealed that epileptic seizures induce a reorganization of the interactions from brain to heart, as the unique predictability of HRV originated from the ipsi-EEG for the δ waves and from the contra-EEG for the α waves in the pre-ictal phase, while these patterns were reversed after the seizure. Significance. These results highlight the importance of considering higher-order interactions elicited by PID for the study of the neuro-autonomic effects of focal epilepsy, and may have neurophysiological and clinical implications.

Real-world Use of Radiation for Newly Diagnosed Brain Metastases in Patients With ALK-positive Lung Cancer Receiving First-line ALK Inhibitor

Management paradigms now allow for systemic targeted drugs before central nervous system (CNS)-directed radiation therapy (RT) in selected asymptomatic patients with non-small cell lung cancer (NSCLC) and brain metastases (BM). We aimed to quantify how novel targeted agents with improved CNS activity, such as second-generation anaplastic lymphoma kinase (ALK) inhibitors (eg, alectinib), might affect the role of CNS-directed RT. This retrospective, observational, real-world, patterns-of-care study used a nationwide, electronic, health record-derived, de-identified, longitudinal database. A random sample of patients with ALK+ advanced NSCLC and BM on first-line ALK-inhibitor monotherapy between January 1, 2014 and August 31, 2019 were included. Using an index date of the first instance of BM, the outcome was brain-directed local treatment within 4 months. Trends over time were reported and tested using multivariable modified Poisson regression with robust error variance, including an indicator during or after 2017 (when alectinib was approved). Of the 352 included patients, 146 had BM. In addition, 104 patients received CNS-directed local therapy, and 42 did not. The majority of patients (89.4%) were treated with RT alone. Of those receiving RT, stereotactic radiosurgery monotherapy was the most common (53%), followed by whole brain RT alone (39%). On multivariable analysis, patients who had their first BM during or after 2017 had a decreased rate of receiving local BM treatment versus those before 2017 with an adjusted incidence rate ratio of 0.63 (95% confidence interval [CI], 0.41-0.95; P = .026). We found no change in the proportion of BM treated with whole brain RT during or after 2017 versus before (adjusted incidence rate ratio: 0.70; 95% CI: 0.24-2.06; P = .517). We found decreasing use of CNS-directed RT in patients with NSCLC with new BM on first-line ALK inhibitors. Clinical outcomes for these patients require continued investigation, because physicians may become increasingly comfortable deferring upfront local therapy for BM in lieu of novel targeted agents with improved CNS activity.

Comparison of different emotion stimulation modalities: an EEG signal analysis.

Emotions processing is a complex mechanism that involves different physiological systems. In particular, the Central Nervous System (CNS) is considered to play a key role in this mechanism and one of the main modalities to study the CNS activity is the Electroencephalographic signal (EEG). To elicit emotions, different kinds of stimuli can be used e.g.: audio, visual or a combination of the two. Literature studies focus more on the correct classification of the different types of emotions or which kind of stimulation gives the best performance in terms of classification accuracy. However, it is still unclear how the different stimuli elicit the emotions and which are the results in terms of brain activity. In this paper, we analysed and compared EEG signals given by eliciting emotions using audio and visual stimuli or a combination of the latter two. Data were collected during experiments conducted in our laboratories using IAPS and IADS dataset. Our study confirmed literature physiological studies about emotions highlighting higher brain activity in the frontal and central regions and in the δ and θ bands for each kind of stimulus. However, audio stimulation was found to have higher responses when compared to the other two modalities of stimulation in almost all the comparisons performed. Higher values of the δ/β ratios, an index related to negative emotions, have been achieved when using only sounds as stimuli. Moreover, the same type of stimuli, resulted in higher δ-β coupling, suggesting a better attention control. We concluded that stimulating subjects without letting them know (seeing) what is actually happening may give a higher perception of emotions, even if this mechanism remains highly subjective. Clinical Relevance- This paper suggests that audio stimuli may give higher perception of the elicited emotion resulting in higher brain activity in the physiological areas and more focused subjects. Thus using only audio in emotion related studies may give more reliable and consistent results.

Verification EVestG recordings are vestibuloacoustic signals.

IntroductionNeural dysfunction is associated with aberrant nerve firing; thus, electrodiagnosis has the potential for objective diagnosis and quantification of neural dysfunction. Electrical stimulation alters nerve firing and may also have treatment potential. This article outlines some findings related to electrodiagnosis and electrical stimulation of the ear. The quasi‐synchronous firing of many vestibuloacoustic nerve fibers can produce an extracellular potential defined as a field potential (FP). Electrovestibulography (EVestG) is a method to record vestibuloacoustic signals and detect the associated FPs. A clear picture of the muscle‐, EEG‐, saccade‐related, or other artefactual origins, and the physiologic basis of FPs recorded with EVestG, is evolving. EVestG was applied to demonstrate the effect of electrical stimulation on spontaneous FPs in the ear canal.MethodsBilateral EVestG recordings were conducted on 14 guinea pigs before and after stimulation with 3–0.5 mA ipsilateral anodal electrical pulses before and after ablation via unilateral Scarpa's ganglionectomy to elucidate the origin of the EVestG recorded spontaneous FPs.ResultsAnodal electrical stimulation suppresses the recorded activity. There was a significant reduction of the level of recorded signal observed following anodal stimulation on the ablated but not the intact side.ConclusionElectrical stimulation of the external auditory canal reduces spontaneous electrical activity in the ear canal, some of which is due to central nervous system activity. The EVestG recorded FPs have a major vestibuloacoustic component.

REL-1017 (esmethadone; d-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats

REL-1017 (esmethadone, d-methadone) is the opioid-inactive d-isomer of racemic d,l-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-d-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical “extinction burst” pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.

Clinical efficacy of osimertinib in EGFR-mutant non-small cell lung cancer with distant metastasis

BackgroundOsimertinib—the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)—has been widely used as a first-line treatment for patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib demonstrated central nervous system activity in patients with brain metastasis; however, its efficacy against other distant metastatic organs, including bone and liver, remains unclear. Therefore, we retrospectively analyzed the clinical efficacy of osimertinib in these patients in comparison to other EGFR-TKIs.MethodsClinical data of patients with advanced NSCLC receiving gefitinib/erlotinib (n = 183), afatinib (n = 55), or osimertinib (n = 150) at five medical institutions were retrospectively assessed for progression-free survival (PFS), overall survival (OS), and best overall response rate (ORR).ResultsIn univariate and multivariate analyses, most distant metastases, including the brain and bone, were unrelated to the therapeutic efficacy of osimertinib, although liver metastasis and L858R mutation were independently associated with shorter PFS. PFS and OS in patients with liver metastases were significantly shorter than those in patients without liver metastases (PFS: 7.4 vs. 19.7 months, OS: 12.1 months vs. not reached, respectively). Osimertinib provided significantly longer PFS in patients with brain or bone metastasis and exon 19 deletion than the other EGFR-TKIs. The PFS of patients with liver metastases was not significantly different among the three EGFR-TKI groups. Furthermore, the ORR of osimertinib in patients with liver metastases was significantly attenuated, and the effectiveness was similar to 1st- or 2nd -generation EGFR-TKIs.ConclusionOsimertinib provided better clinical benefits than 1st- and 2nd-generation EGFR-TKIs for patients with EGFR-mutant NSCLC, particularly those with brain or bone metastases and exon 19 deletion; however, its efficacy against liver metastasis was remarkably attenuated. New therapeutic developments for patients with EGFR-mutant NSCLC with liver metastases are needed.

A phase 1/2 study of the highly selective EGFR inhibitor, BLU-701, in patients with EGFR-mutant non–small cell lung cancer (NSCLC).

TPS9142 Background: Although 3rd-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, are highly effective in front-line metastatic EGFR-mutated ( EGFRm) NSCLC, treatment resistance ultimately occurs, including the emergence of the on-target C797X mutation for which there are no approved TKIs. BLU-701 is an investigational, reversible, brain-penetrant, wildtype-sparing oral TKI with nanomolar potency on common activating (exon 19 deletion and L858R) and C797X resistance mutations (Tavera L et al. AACR 2022). BLU-701 has shown promising preclinical data, including antitumor central nervous system (CNS) activity that may improve patient outcomes. Additionally, combining BLU-701 with standard of care therapies may provide enhanced disease control across multiple lines of treatment, including against heterogenous tumors, in patients with EGFRm NSCLC. Methods: HARMONY (NCT05153408) is an ongoing, global phase 1/2, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BLU-701 as a monotherapy or in combination with osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC. Key inclusion criteria include patients ≥18 years of age with metastatic EGFRm NSCLC; Eastern Cooperative Oncology Group performance status 0–1; and previous treatment with ≥1 EGFR-targeted TKI. Patients in the phase 2 monotherapy part must harbor an EGFR C797X resistance mutation (locally assessed). Key exclusion criteria are tumors harboring EGFR T790M mutations, EGFR exon 20 insertions, or other known driver alterations, including KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET. Phase 1 primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D), and safety. The phase 2 primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include ORR (phase 1), duration of response, and PK/PD (phase 1 and phase 2); disease control rate, progression-free survival, overall survival, antitumor CNS activity, and safety (phase 2). The phase 1 dose escalation will adopt a Bayesian optimal interval design. Patients will be enrolled into 3 treatment cohorts: part 1A (n≈40–80; BLU-701), part 1B (n≈35; BLU-701 + osimertinib), and part 1C (n≈18; BLU-701 + carboplatin and pemetrexed). Patients in the phase 2 dose expansion (n≈24) will be treated at the RP2D of BLU-701 as monotherapy. Patients may receive treatment until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment in this study has started, and sites will be open across North America, Europe, and Asia. Clinical trial information: NCT05153408.

Phase 1/2 study of BLU-451, a central nervous system (CNS) penetrant, small molecule inhibitor of EGFR, in incurable advanced cancers with EGFR exon 20 insertion (ex20ins) mutations.

TPS9155 Background: Oncogenic EGFR 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, CNS metastases are a challenge with EGFR ex20ins NSCLC and are associated with poor outcomes. While two EGFR ex20ins-targeting drugs were recently approved by the FDA (amivantamab and mobocertinib), neither have established CNS activity. BLU-451 is a CNS penetrant, wild type-sparing, covalent small molecule inhibitor of EGFR ex20ins as well as atypical (G719C, G719S, L861Q) and common EGFR mutants. Preclinical data have shown BLU-451 to have potent antitumor activity, including in an intracranial xenograft model, which has led to its clinical development in EGFR-mutant NSCLC. Methods: BLU-451-1101 (NCT05241873) is a phase 1/2, global, open-label study designed to evaluate single-agent BLU-451 in patients with NSCLC harboring EGFR ex20ins that has progressed following prior treatment for incurable recurrent or metastatic disease. Patients with Eastern Cooperative Oncology Group performance status 0–1 and EGFR ex20ins, exon 18 G719X or exon 21 L861Q mutant NSCLC (phases 1 and 2) or other cancers except primary CNS tumors (phase 1 only) are eligible. Patients with known ROS, RAF, ALK, or EGFR C797S mutations will be excluded. Stable, asymptomatic brain metastases are permitted, and active asymptomatic brain metastases are permitted in specific cohorts. Primary endpoints are determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and tolerability (phase 1), in addition to evaluation of antitumor activity at the RP2D by RECIST v1.1 (phase 2). Secondary endpoints are evaluation of pharmacokinetics (PK) and antitumor activity by RECIST v1.1.(phase 1) and PK, safety, tolerability, and CNS antitumor activity (phase 2). Dose escalation will utilize a 3+3 design with up to 6 patients per cohort in phase 1 dose escalation and up to 12 per cohort in phase 1 dose expansion. Phase 2 will enroll patients in 3 cohorts (n = 18 each): patients with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned for approximately 40 centers in North America, the Asia-Pacific region, and/or Europe. Clinical trial information: NCT05241873.

An enriched environment re-establishes metabolic homeostasis by reducing obesity-induced inflammation.

ABSTRACTObesity can lead to chronic inflammation in different tissues, generating insulin and leptin resistance and alterations in glucose and lipid metabolism, favoring the development of degenerative diseases, including type II diabetes. Congruently, the inflammatory signaling inhibition prevents the development of obesity and restores insulin sensitivity. Via the enhancement of central nervous system activity, an enriched environment (EE) has beneficial effects on learning and memory as well as on immune cell functions and inflammation in different disease models. Here, we explored whether an EE can restore energy balance in obese mice that previously presented metabolic alterations. We discovered that an EE improved glucose metabolism, increased insulin signaling in liver, and reduced hepatic steatosis and inflammation, and increased lipolysis and browning in the white adipose tissue of high-fat diet (HFD)-fed mice. Finally, we found reduced inflammatory signaling and increased anorexigenic signaling in the hypothalamus of HFD-fed mice exposed to an EE. These data indicate that an EE is able to restore the metabolic imbalance caused by HFD feeding. Thus, we propose EE as a novel therapeutic approach for treating obesity-related metabolic alterations.This article has an associated First Person interview with the first author of the paper.

Hypoxia Augments TRPM3‐mediated Calcium Influx in Vagal Sensory Neurons

Exposure to low systemic oxygen (hypoxia, Hx) elevates blood pressure, heart rate and respiration via reflex sensory and central nervous system activation. We have shown transient receptor potential (TRP) vanilloid channels contribute to afferent‐evoked activation of the brainstem nucleus tractus solitarii (nTS) following chronic Hx. Short sustained Hx exposure (10% O2, 24hr) in rats also enhances nTS activity, although the mechanisms are not completely understood. Recent evidence from others shows TRP melastatin 3 (TRPM3) channels contribute to afferent activity and nTS glutamate signaling, but their role in afferent signaling in Hx is unknown. We hypothesize that TRPM3 increases afferent neuronal activity in nTS‐projecting nodose ganglia (NG) neurons, and its contribution is elevated following Hx. Rats were exposed to either in vivo normal room air (normoxia) or 24‐hr of 10% O2 (Hx). A subset of NG neurons from normoxic rats were exposed to in vitro incubation for 24‐hr in 21% or 1% O2, 5% CO2. Intracellular calcium (Ca2+) of dissociated NG neurons was monitored via Fura‐2 fluorescence imaging. TRPM3 was activated via 1‐min bath application of Pregnenolone sulfate (Preg, 30 and 100 µM) or CIM0216 (5 ‐ 20 µM). The increase in cellular fluorescence to Preg or CIM0216 was normalized to that of its prior baseline fluorescence (ΔF/F%). NG neurons were also exposed to vehicle (Veh) alone and their Ca2+ ΔF/F% responses were used as the threshold for TRPM3 responders under comparable timeframes. RNAScope identified TRPM3 transcripts in the normoxic NG. Veh alone did not alter Ca2+ from their initial baseline (ΔF/F%, less than 102.5% increase across all preparations). Activation of TRPM3 via Preg (30 and 100 µM) elevated Ca2+ in 51% and 55% of NG neurons by a similar magnitude [120.4 ± 3.8% and 116.6 ± 3.0% (mean ± SEM), respectively]. CIM0216 also augmented Ca2+ with the greatest response occurring during 20 µM (~56% of NG neurons, 115.6 ± 3.1% elevation). Preg responses were significantly reduced by pre‐application of the TRPM3 antagonist ononetin (20 µM; Preg, 125.9 ± 7.7% vs. ononetin + Preg, 101.7 ± 0.6%), confirming drug specificity. Elevated Ca2+ by 30 µM Preg was also eliminated by bathing cells in 0 mM Ca2+ (reduced to 100.9 ± 0.4%) suggesting Ca2+ elevation occurs via opening of membrane‐bound TRPM3. In NG neurons isolated from Hx‐exposed rats, the Preg‐induced elevation of Ca2+ was significantly greater than their paired normoxic‐exposed rats (134.1 ± 4.2% vs 118.1 ± 3.9%), although the number of responders were comparable (40% vs 43%). To determine if the increase in TRPM3 Ca2+ responses to in vivo Hx was due to the reduction of oxygen or the reflex‐induced change in neuronal activity, cells were isolated then incubated in either 21% or 1% O2 for 24 hrs. Following 24 hr in vitro Hx, 30 µM Preg enhanced Ca2+ more than in 24 hr normoxic controls (115.3 ± 2.2% vs 108.1 ± 0.1%). The proportion of Preg responders was similar between groups (58% vs 61%). Altogether, these results suggest a Hx specific increase in TRPM3 function, driven by the influx of extracellular calcium.

LRRK‐2 Inhibition By PF06447475 Treatment Reduces Neuronal Damage and Immune Response After Spinal Cord Trauma

Spinal Cord Injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade and immune system. Dysregulated or non‐resolving inflammatory processes can affect neuronal homeostasis and drive immune cells stimulation. The leucine‐rich‐repeat kinase 2 (LRRK2) is a gene associated with the progression of Parkinson’s disease (PD), and its kinase activity was found to be upregulated after instigated inflammation of the Central Nervous System (CNS) and immune system activation. Here, we aimed to investigate the efficacy of PF‐06447475, an LRRK2 inhibitor, by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord at T6‐T8 levels, then mice were treated with PF‐06447475 (2.5‐5 and 10 mg/kg o.s) 1 and 6 hrs after SCI. We found that PF‐06447475 treatments at the higher doses (5 and 10 mg/kg) showed great abilities to reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. In addition, cytokines expression levels including interleukins (IL‐1, IL‐6, IL‐10 and12),interferong(IFN‐g)and tumor necrosis factor‐α (TNF‐α secreted and released by immune cells after trauma were decreased by LRRK‐2 inhibitor treatments. Moreover, the accumulation of CD4+and CD8+cells throughout the spinal cord lesion site of SCI mice was reduced by PF‐06447475 oral administration at the dose of 10 mg/kg. Taken together, our results suggest that exist a mutual correlation between LRRK2, neurodegeneration and immunity and that LRRK2 inhibition could have direct effects on the intervention of neuroinflammatory disorders.

Mapping and specific viral targeting of peripheral pancreatic innervation

Neuronal inputs from central nervous system (CNS) are essential in regulating pancreatic endocrine function. It has been shown that perturbation of CNS activity alters pancreatic hormone release. CNS and peripheral organs constantly communicate through the peripheral nervous system (PNS), which can be divided into autonomic efferent (parasympathetic and sympathetic) and afferent sensory nervous systems. While we know that the pancreas is densely innervated by the PNS, we lack a comprehensive map of peripheral ganglia providing inputs to the pancreas. These data could provide crucial information about pancreatic function. Published studies suggest parasympathetic inputs to the pancreas lower blood glucose by enhancing insulin secretion. On the other hand, sympathetic action results in increased blood glucose levels by stimulating glucagon secretion and inhibiting insulin. However, these studies are based on electrical stimulation or transection of peripheral splachnic and vagal nerves that may affect the activity of other metabolically active organs (liver, stomach, intestine,). Highly targeted modulation of specific pancreatic nerve activity in health and pancreatic diseases requires new approaches.In the present project, we provide a detailed map of the distribution of peripheral pancreas‐innervating neurons using retrograde tracing, tissue clearing and 3D imaging techniques (Idisco+). We show that a substantial pancreatic innervation (Fig 1b) with significant neuronal populations in sympathetic, parasympathetic and sensory ganglia projecting to pancreatic tissue (Fig 1 c,d). In addition, we achieved targeted gene delivery to specific pancreatic efferent and afferent pathways by optimizing adeno‐associated viral serotypes (AAV), promoters, titers and delivery (Fig2 a‐d). By utilizing our optimized approach, we show that highly targeted chemogenetic neural activation of intrapancreatic parasympathetic cholinergic neurons increased plasma insulin and significantly improved glucose tolerance in male mice (Fig 2 e,f). Additionally, using a dual viral strategy to specifically target pancreas‐projecting sympathetic neurons, we demonstrated that targeted activation of pancreas‐projecting sympathetic neurons impaired glucose tolerance in male mice (Fig 2g,h).Our innovative viral approaches allow highly targeted gene expression and neuromodulation of defined pancreatic nerves. These methodologies will allow examination of functional roles of pancreatic parasympathetic and sympathetic innervation in glucose metabolism as well as in digestion (exocrine function). Our work also allow for future studies to determine the specific contribution of pancreatic innervation to metabolic diseases, pancreatic inflammation and cancer.