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Aim:Methyl eugenol is a major active component extracted from the Chinese herb Asari Radix et Rhizoma, which has been used to treat toothache and other pain. Previous in vivo studies have shown that methyl eugenol has anesthetic and antinociceptive effects. The aim of this study was to determine the possible mechanism underlying its effect on nervous system disorders.Methods:The direct interaction of methyl eugenol with Na+ channels was explored and characterized using electrophysiological recordings from Nav1.7-transfected CHO cells.Results:In whole-cell patch clamp mode, methyl eugenol tonically inhibited peripheral nerve Nav1.7 currents in a concentration- and voltage-dependent manner, with an IC50 of 295 μmol/L at a −100 mV holding potential. Functionally, methyl eugenol preferentially bound to Nav1.7 channels in the inactivated and/or open state, with weaker binding to channels in the resting state. Thus, in the presence of methyl eugenol, Nav1.7 channels exhibited reduced availability for activation in a steady-state inactivation protocol, strong use-dependent inhibition, enhanced binding kinetics, and slow recovery from inactivation compared to untreated channels. An estimation of the affinity of methyl eugenol for the resting and inactivated states of the channel also demonstrated that methyl eugenol preferentially binds to inactivated channels, with a 6.4 times greater affinity compared to channels in the resting state. The failure of inactivated channels to completely recover to control levels at higher concentrations of methyl eugenol implies that the drug may drive more drug-bound, fast-inactivated channels into drug-bound, slow-inactivated channels.Conclusion:Methyl eugenol is a potential candidate as an effective local anesthetic and analgesic. The antinociceptive and anesthetic effects of methyl eugenol result from the inhibitory action of methyl eugenol on peripheral Na+ channels. [ABSTRACT FROM AUTHOR]

Cannabinoid receptors (CB1Rs) are present in glomeruli of the main olfactory bulb. The functions of CB1Rs and their endogenous activators, endocannabinoids, for glomerular signaling are unknown. Glomeruli contain at least three types of neurons: periglomerular (PG), external tufted (ET), and short-axon (SA) cells. PG cells form inhibitory GABAergic dendrodendritic synapses with ET cells. ET cells form excitatory glutamatergic dendrodendritic synapses with PG and SA cells. In mouse brain slices, we used whole-cell patch-clamp recordings to study the role of CB1Rs in regulating PG and ET cells. Cannabinoids displayed strong, direct inhibitory effects on PG cells and weak effects on ET cells. Single pulses or a train of pulses of depolarizing current injected into an ET cell evoked suppression of IPSCs. This suggests retrograde endocannabinoid signaling, namely, depolarization-induced suppression of inhibition (DSI) in ET cells. Our results support the hypothesis that burst firing of ET cells triggers the release of endocannabinoids which in turn directly inhibit PG cells and reduce GABA release from PG cells. This, in turn, can result in a transient reduction of PG cell inhibitory input to ET cells. [ABSTRACT FROM AUTHOR]

Deals with a study which explored the effects of serotonin on projection neurons in the sexually dimorphic macroglomerular complex in the antennal lobe of the male moth Manduca sexta. Materials and methods; Results; Discussion and conclusion.

In the main olfactory bulb, several populations of granule cells (GCs) can be distinguished based on the soma location either superficially, interspersed with mitral cells within the mitral cell layer (MCL), or deeper, within the GC layer (GCL). Little is known about the physiological properties of superficial GCs (sGCs) vs. deep GCs (dGCs). Here, we used patch-clamp recording methods to explore the role of Group I metabotropic glutamate receptors (mGluRs) in regulating the activity of GCs in slices from wildtype and mGluR -/- mutant mice. In wildtype mice, bath application of the selective Group I mGluR agonist DHPG depolarized and increased the firing rate of both GC subtypes. In the presence of blockers of fast synaptic transmission (APV, CNQX, gabazine), DHPG directly depolarized both GC subtypes. The two GC subtypes responded differentially to DHPG in mGluR1-/- and mGluR5-/- mice, however. DHPG depolarized sGCs in slices from mGluR5-/- mice, but it had no effect on sGCs in slices from mGluR1-/- mice. By contrast, DHPG depolarized dGCs in slices from mGluR1-/- mice, but it had no effect on dGCs in slices from mGluR5-/- mice. Previous studies have shown that mitral cells express mGluR1, but not mGluR5. The results suggest that sGCs are more similar to mitral cells than dGCs in terms of mGluR expression. [ABSTRACT FROM AUTHOR]

Circadian rhythms are biological rhythms that originate from the "master circadian clock," called the suprachiasmatic nucleus (SCN). SCN orchestrates the circadian rhythms using light as a chief zeitgeber, enabling humans to synchronize their daily physio-behavioral activities with the Earth's light-dark cycle. However, chronic/ irregular photic disturbances from the retina via the retinohypothalamic tract (RHT) can disrupt the amplitude and the expression of clock genes, such as the period circadian clock 2, causing circadian rhythm disruption (CRd) and associated neuropathologies. The present review discusses neuromodulation across the RHT originating from retinal photic inputs and modulation offered by endocannabinoids as a function of mitigation of the CRd and associated neuro-dysfunction. Literature indicates that cannabinoid agonists alleviate the SCN's ability to get entrained to light by modulating the activity of its chief neurotransmitter, i.e., γ-aminobutyric acid, thus preventing light-induced disruption of activity rhythms in laboratory animals. In the retina, endocannabinoid signaling modulates the overall gain of the retinal ganglion cells by regulating the membrane currents (Ca2+, K+, and Cl- channels) and glutamatergic neurotransmission of photoreceptors and bipolar cells. Additionally, endocannabinoids signalling also regulate the high-voltage-activated Ca2+ channels to mitigate the retinal ganglion cells and intrinsically photosensitive retinal ganglion cells-mediated glutamate release in the SCN, thus regulating the RHT-mediated light stimulation of SCN neurons to prevent excitotoxicity. As per the literature, cannabinoid receptors 1 and 2 are becoming newer targets in drug discovery paradigms, and the involvement of endocannabinoids in light-induced CRd through the RHT may possibly mitigate severe neuropathologies. • Circadian rhythms originate from suprachiasmatic nucleus using light as a chief zeitgeber. • Cannabinoid agonists alleviate SCN's ability entrained by light by modulating neuro-activity. • Endocannabinoids modulate retinal ganglion cells by Ca2+, K+, and Cl- channels and bipolar cells. • Endocannabinoids in light-induced CRd through retino-hypothalamic tract mitigate neuropathologies. • In SCN, endocannabinoids modulate glutamate release via retinohypothalamic tract, rescuing CRd. [ABSTRACT FROM AUTHOR]

Circadian rhythms are 24-hour natural rhythms regulated by the suprachiasmatic nucleus, also known as the "master clock". The retino-hypothalamic tract entrains suprachiasmatic nucleus with photic information to synchronise endogenous circadian rhythms with the Earth's light-dark cycle. However, despite the robustness of circadian rhythms, an unhealthy lifestyle and chronic photic disturbances cause circadian rhythm disruption in the suprachiasmatic nucleus's TTFL loops via affecting glutamate and γ-aminobutyric acid-mediated neurotransmission in the suprachiasmatic nucleus. Recently, considerable evidence has been shown correlating CRd with the incidence of Alzheimer's disease. The present review aims to identify the existence and signalling of endocannabinoids in CRd induced Alzheimer's disease through retino-hypothalamic tract- suprachiasmatic nucleus-cortex. Immunohistochemistry has confirmed the expression of cannabinoid receptor 1 in the suprachiasmatic nucleus to modulate the circadian phases of the master clock. Literature also suggests that cannabinoids may alter activity of suprachiasmatic nucleus by influencing the activity of their major neurotransmitter γ-aminobutyric acid or by interacting indirectly with the suprachiasmatic nucleus's two other major inputs i.e., the geniculo-hypothalamic tract-mediated release of neuropeptide Y and serotonergic inputs from the dorsal raphe nuclei. Besides, the expression of cannabinoid receptor 2 ameliorates cognitive deficits via reduction of tauopathy and microglial activation. In conclusion, endocannabinoids may be identified as a putative target for correcting CRd and decelerating Alzheimer's disease. • SCN generated CRs are robust in nature; lifestyle-related factors, such as chronic photic disturbances, can cause asynchrony in CRs, i.e., CR disruption (CRd). • Numerous evidence correlates CRd with the enhanced risk of dementia. • CRd increases Aβ load in the hippocampus and thalamus, affects the glymphatic pathway and hinders the clearance of Aβ from the CNS. • Endocannabinoid system, a link between CRd and AD has been found to be disrupted in neurodegeneration. CB1 knockout mice were shown to have AD-like symptoms. • ECS plays an essential role in modulating the light-mediated phase shifts of SCN generated CRs. [ABSTRACT FROM AUTHOR]

Salivation is easily taken for granted, but without normal salivation, simple essential tasks such as chewing and swallowing become difficult, with consequences for quality of life, nutrition and oral health. Many important drug classes cause dry mouth as a side effect, contributing substantially to patient non-compliance. Available treatments are mostly palliative. Cannabis user complaints of dry mouth prompted a study that showed that basal salivation is likely regulated by cannabinoid CB1 receptors on neurons that innervate the submandibular gland. But what about stimulated salivation? The adjoining parotid gland releases saliva in response to olfactory or other cues and contributes a large portion of the net salivation in humans. We investigated cannabinoid regulation of stimulated salivation using functional and protein-expression studies in mice. In developing a model of stimulated salivary responses to food-related odorants in mice, we noted sex-dependent responses to food-related cues. Only male mice learned to salivate in response to the odor of peanut butter while only female mice responded to a chocolate hazelnut spread. Both males and females responded to sugar or marmite. Testing peanut butter, we found that the cannabinoid receptor agonist CP55940 (0.5 mg/kg, IP) lowered baseline salivation, as shown previously, but also prevented the odorant-induced increase in salivation. CB1 receptors are expressed in axons innervating the parotid gland, paralleling our findings in the submandibular gland. Notably, we also found that CB1 deletion impaired some responses (those to peanut butter and chocolate hazelnut spread) but not others (sugar or marmite). In mice, the CB1 antagonist SR141716 (4 mg/kg, IP) prevented a previously learned salivary response to peanut butter. We find that CB1 receptors are expressed in a subset of glomeruli in coronal sections of olfactory bulb that may serve as a site of action for scent-specific effects of CB1 receptors. We additionally observe CB1 expression in accessory olfactory bulb. In summary, we find a novel sex-dependence in responses to a subset of food-related odorant cues and that cannabinoid receptors regulate some of these responses. We propose that CB1 receptors act at the parotid gland to inhibit stimulated salivation but also in the olfactory system, where functional CB1 receptors are required for salivary responses to specific appetitive odors., (© 2024. The Author(s).)

Organ and tissue damage can result from injury and disease. How to facilitate regeneration from damage has been a topic for centuries, and still, we are trying to find agents to use for treatments. Two groups of biological substances are known to facilitate wound healing. Phytochemicals with bioactive properties form one group. Many phytochemicals have anti-inflammatory effects and enhance wound healing. Recent studies have described their effects at the gene and protein expression levels, highlighting the receptors and signaling pathways involved. The extremely large number of phytochemicals and the multiple types of receptors they activate suggest a broad range of applicability for their clinical use. The hydrophobic nature of many phytochemicals and the difficulty with chemical stabilization have been a problem. Recent developments in biotechnology and nanotechnology methods are enabling researchers to overcome these problems. The other group of biological substances is extracellular vesicles (EVs), which are now known to have important biological functions, including the improvement of wound healing. The proteins and nanoparticles contained in mammalian EVs as well as the specificity of the targets of microRNAs included in the EVs are becoming clear. Plant-derived EVs have been found to contain phytochemicals. The overlap in the wound-healing capabilities of both phytochemicals and EVs and the differences in their nature suggest the possibility of a combinatorial use of the two groups, which may enhance their effects.

Introduction: There have been large geographical differences in the infection and death rates of COVID-19. Foods and beverages containing high amounts of phytochemicals with bioactive properties were suggested to prevent contracting and to facilitate recovery from COVID-19. The goal of our study was to determine the correlation of the type of foods/beverages people consumed and the risk reduction of contracting COVID-19 and the recovery from COVID-19., Methods: We developed an online survey that asked the participants whether they contracted COVID-19, their symptoms, time to recover, and their frequency of eating various types of foods/beverages. The survey was developed in 10 different languages., Results: The participants who did not contract COVID-19 consumed vegetables, herbs/spices, and fermented foods/beverages significantly more than the participants who contracted COVID-19. Among the six countries (India/Iran/Italy/Japan/Russia/Spain) with over 100 participants and high correspondence between the location of the participants and the language of the survey, in India and Japan the people who contracted COVID-19 showed significantly shorter recovery time, and greater daily intake of vegetables, herbs/spices, and fermented foods/beverages was associated with faster recovery., Conclusions: Our results suggest that phytochemical compounds included in the vegetables may have contributed in not only preventing contraction of COVID-19, but also accelerating their recovery., (Copyright © 2024 Koyama, Joseph, Shields, Heinbockel, Adhikari, Kaur, Kumar, Alizadeh, Bhutani, Calcinoni, Mucignat-Caretta, Chen, Cooper, Das, Rohlfs Domínguez, Guàrdia, Klyuchnikova, Laktionova, Mori, Namjoo, Nguyen, Özdener, Parsa, Özdener Poyraz, Strub, Taghizadeh-Hesary, Ueha and Voznessenskaya.)

Mitral cells (MCs) in the main olfactory bulb relay odor information to higher-order olfactory centers by encoding the information in the form of action potentials. The firing patterns of these cells are influenced by both their intrinsic properties and their synaptic connections within the neural network. However, reports on MC firing patterns have been inconsistent, and the mechanisms underlying these patterns remain unclear. Using whole-cell patch-clamp recordings in mouse brain slices, we discovered that MCs exhibit two types of integrative behavior: regular/rhythmic firing and bursts of action potentials. These firing patterns could be transformed both spontaneously and chemically. MCs with regular firing maintained their pattern even in the presence of blockers of fast synaptic transmission, indicating this was an intrinsic property. However, regular firing could be transformed into bursting by applying GABA A receptor antagonists to block inhibitory synaptic transmission. Burst firing could be reverted to regular firing by blocking ionotropic glutamate receptors, rather than applying a GABA A receptor agonist, indicating that ionotropic glutamatergic transmission mediated this transformation. Further experiments on long-lasting currents (LLCs), which generated burst firing, also supported this mechanism. In addition, cytoplasmic Ca 2+ in MCs was involved in the transformation of firing patterns mediated by glutamatergic transmission. Metabotropic glutamate receptors also played a role in LLCs in MCs. These pieces of evidence indicate that odor information can be encoded on a mitral cell (MC) platform, where it can be relayed to higher-order olfactory centers through intrinsic and dendrodendritic mechanisms in MCs.

Background: Smell disorders are commonly reported with COVID-19 infection. The smell-related issues associated with COVID-19 may be prolonged, even after the respiratory symptoms are resolved. These smell dysfunctions can range from anosmia (complete loss of smell) or hyposmia (reduced sense of smell) to parosmia (smells perceived differently) or phantosmia (smells perceived without an odor source being present). Similar to the difficulty that people experience when talking about their smell experiences, patients find it difficult to express or label the symptoms they experience, thereby complicating diagnosis. The complexity of these symptoms can be an additional burden for patients and health care providers and thus needs further investigation., Objective: This study aims to explore the smell disorder concerns of patients and to provide an overview for each specific smell disorder by using the longitudinal survey conducted in 2020 by the Global Consortium for Chemosensory Research, an international research group that has been created ad hoc for studying chemosensory dysfunctions. We aimed to extend the existing knowledge on smell disorders related to COVID-19 by analyzing a large data set of self-reported descriptive comments by using methods from natural language processing., Methods: We included self-reported data on the description of changes in smell provided by 1560 participants at 2 timepoints (second survey completed between 23 and 291 days). Text data from participants who still had smell disorders at the second timepoint (long-haulers) were compared with the text data of those who did not (non-long-haulers). Specifically, 3 aims were pursued in this study. The first aim was to classify smell disorders based on the participants' self-reports. The second aim was to classify the sentiment of each self-report by using a machine learning approach, and the third aim was to find particular food and nonfood keywords that were more salient among long-haulers than those among non-long-haulers., Results: We found that parosmia (odds ratio [OR] 1.78, 95% CI 1.35-2.37; P<.001) as well as hyposmia (OR 1.74, 95% CI 1.34-2.26; P<.001) were more frequently reported in long-haulers than in non-long-haulers. Furthermore, a significant relationship was found between long-hauler status and sentiment of self-report (P<.001). Finally, we found specific keywords that were more typical for long-haulers than those for non-long-haulers, for example, fire, gas, wine, and vinegar., Conclusions: Our work shows consistent findings with those of previous studies, which indicate that self-reports, which can easily be extracted online, may offer valuable information to health care and understanding of smell disorders. At the same time, our study on self-reports provides new insights for future studies investigating smell disorders., (©Nick S Menger, Arnaud Tognetti, Michael C Farruggia, Carla Mucignat, Surabhi Bhutani, Keiland W Cooper, Paloma Rohlfs Domínguez, Thomas Heinbockel, Vonnie D C Shields, Anna D'Errico, Veronica Pereda-Loth, Denis Pierron, Sachiko Koyama, Ilja Croijmans. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 10.05.2024.)

Purpose: This study aimed to determine if time-efficient, high-resistance inspiratory muscle strength training (IMST), comprising 30 inhalation-resisted breaths per day, improves cardiorespiratory fitness, exercise tolerance, physical function, and/or regional body composition in healthy midlife and older adults., Methods: We performed a double-blind, randomized, sham-controlled clinical trial (NCT03266510) testing 6 wk of IMST (30 breaths per day, 6 d·wk -1 , 55%-75% maximal inspiratory pressure) versus low-resistance sham training (15% maximal inspiratory pressure) in healthy men and women 50-79 yr old. Subjects performed a graded treadmill exercise test to exhaustion, physical performance battery (e.g., handgrip strength, leg press), and body composition testing (dual x-ray absorptiometry) at baseline and after 6 wk of training., Results: Thirty-five participants (17 women, 18 men) completed high-resistance IMST ( n = 17) or sham training ( n = 18). Cardiorespiratory fitness (V̇O 2peak ) was unchanged, but exercise tolerance, measured as treadmill exercise time during a graded exercise treadmill test, increased with IMST (baseline, 539 ± 42 s; end intervention, 606 ± 42 s; P = 0.01) but not sham training (baseline, 562 ± 39 s; end intervention, 553 ± 38 s; P = 0.69). IMST increased peak RER (baseline, 1.09 ± 0.02; end intervention, 1.13 ± 0.02; P = 0.012), peak ventilatory efficiency (baseline, 25.2 ± 0.8; end intervention, 24.6 ± 0.8; P = 0.036), and improved submaximal exercise economy (baseline, 23.5 ± 1.1 mL·kg -1 ⋅min -1 ; end intervention, 22.1 ± 1.1 mL·kg -1 ⋅min -1 ; P < 0.001); none of these factors were altered by sham training (all P > 0.05). Changes in plasma acylcarnitines (targeted metabolomics analysis) were consistently positively correlated with changes in exercise tolerance after IMST but not sham training. IMST was associated with regional increases in thorax lean mass (+4.4%, P = 0.06) and reductions in trunk fat mass (-4.8%, P = 0.04); however, peripheral muscle strength, muscle power, dexterity, and mobility were unchanged., Conclusions: These data suggest that high-resistance IMST is an effective, time-efficient lifestyle intervention for improving exercise tolerance in healthy midlife and older adults., (Copyright © 2023 by the American College of Sports Medicine.)

Aging is associated with increased risk for cognitive decline and dementia due in part to increases in systolic blood pressure (SBP) and cerebrovascular dysfunction. High-resistance inspiratory muscle strength training (IMST) is a time-efficient, intensive respiratory training protocol (30 resisted inspirations/day) that lowers SBP and improves peripheral vascular function in midlife/older adults with above-normal SBP. However, whether, and by what mechanisms, IMST can improve cerebrovascular function is unknown. We hypothesized that IMST would increase cerebrovascular reactivity to hypercapnia (CVR to CO 2 ), which would coincide with changes to the plasma milieu that improve brain endothelial cell function and enhance cognitive performance (NIH Toolbox). We conducted a 6-wk double-blind, randomized, controlled clinical trial investigating high-resistance IMST [75% maximal inspiratory pressure (PI max ); 6×/wk; 4 females, 5 males] vs. low-resistance sham training (15% PI max ; 6×/wk; 2 females, 5 males) in midlife/older adults (age 50-79 yr) with initial above-normal SBP. Human brain endothelial cells (HBECs) were exposed to participant plasma and assessed for acetylcholine-stimulated nitric oxide (NO) production. CVR to CO 2 increased after high-resistance IMST (pre: 1.38 ± 0.66 cm/s/mmHg; post: 2.31 ± 1.02 cm/s/mmHg, P = 0.020). Acetylcholine-stimulated NO production increased in HBECs exposed to plasma from after vs. before the IMST intervention [pre: 1.49 ± 0.33; post: 1.73 ± 0.35 arbitrary units (AU); P < 0.001]. Episodic memory increased modestly after the IMST intervention (pre: 95 ± 13; post: 103 ± 17 AU; P = 0.045). Cerebrovascular and cognitive function were unchanged in the sham control group. High-resistance IMST may be a promising strategy to improve cerebrovascular and cognitive function in midlife/older adults with above-normal SBP, a population at risk for future cognitive decline and dementia. NEW & NOTEWORTHY Midlife/older adults with above-normal blood pressure are at increased risk of developing cognitive decline and dementia. Our findings suggest that high-resistance inspiratory muscle strength training (IMST), a novel, time-efficient (5-10 min/day) form of physical training, may increase cerebrovascular reactivity to CO 2 and episodic memory in midlife/older adults with initial above-normal blood pressure.

Throughout the animal kingdom, our two chemical senses, olfaction and gustation, are defined by two primary factors: genomic architecture of the organisms and their living environment. During the past three years of the global COVID-19 pandemic, these two sensory modalities have drawn much attention at the basic science and clinical levels because of the strong association of olfactory and gustatory dysfunction with viral infection. Loss of our sense of smell alone, or together with a loss of taste, has emerged as a reliable indicator of COVID-19 infection. Previously, similar dysfunctions have been detected in a large cohort of patients with chronic conditions. The research focus remains on understanding the persistence of olfactory and gustatory disturbances in the post-infection phase, especially in cases with long-term effect of infection (long COVID). Also, both sensory modalities show consistent age-related decline in studies aimed to understand the pathology of neurodegenerative conditions. Some studies using classical model organisms show an impact on neural structure and behavior in offspring as an outcome of parental olfactory experience. The methylation status of specific odorant receptors, activated in parents, is passed on to the offspring. Furthermore, experimental evidence indicates an inverse correlation of gustatory and olfactory abilities with obesity. Such diverse lines of evidence emerging from basic and clinical research studies indicate a complex interplay of genetic factors, evolutionary forces, and epigenetic alterations. Environmental factors that regulate gustation and olfaction could induce epigenetic modulation. However, in turn, such modulation leads to variable effects depending on genetic makeup and physiological status. Therefore, a layered regulatory hierarchy remains active and is passed on to multiple generations. In the present review, we attempt to understand the experimental evidence that indicates variable regulatory mechanisms through multilayered and cross-reacting pathways. Our analytical approach will add to enhancement of prevailing therapeutic interventions and bring to the forefront the significance of chemosensory modalities for the evaluation and maintenance of long-term health.

In a preregistered, cross-sectional study, we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n = 4148) or negative (C19-; n = 546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean ± SD, C19+: -82.5 ± 27.2 points; C19-: -59.8 ± 37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC = 0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4 < OR < 10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ethanol (EtOH) is one of the most frequently abused drugs with heavy health, economic, and societal burdens. Although moderate to low EtOH may have some neuroprotective effects, heavy EtOH consumption associated with high blood alcohol level (BAL) can be quite detrimental. The brain is particularly vulnerable to the damaging effects of high BAL, leading to neuronal loss, cognitive, and behavioral deficits. Although the exact causes of these detriments are not fully elucidated, it is believed that damage to the cholinergic system is at least partially responsible for the cognitive impairment. Thus, high BAL may result in selective apoptotic damage to the cholinergic neurons. Donepezil (DON), a centrally acting, reversible and non-competitive acetylcholinesterase (AChE) inhibitor, approved for use in Alzheimer's disease (AD), may also attenuate EtOH-induced cognitive impairment. Cognitive effects of DON might be due to an anti-apoptotic activity as some AChE inhibitors have been shown to have this property. The aim of this study was to determine whether DON might protect against EtOH-induced toxicity and whether such protection might be apoptotically mediated. We exposed the human neuroblastoma-derived, SH-SY5Y cells to a relatively high concentration of EtOH (500 mM) for 24 h and evaluated the effects of two concentrations of DON (0.1 and 1.0 μM) on alcohol-induced toxicity and caspase-3, an apoptotic marker. We found a dose-dependent protection of DON against EtOH-induced toxicity as well as dose-dependent attenuation of EtOH-induced increases in caspase-3 levels. Thus, DON may inhibit apoptosis as well as alcohol-induced toxicity.

Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5-200 μM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation.

Alpha (α)-asarone, a major effective component isolated from the Chinese medicinal herb Acorus tatarinowii, is clinically used as medication for treating epilepsy, cough, bronchitis, and asthma. In the present study, we demonstrated that α-asarone targets central nervous system GABAA receptor as well as voltage-gated Na(+) channels. Using whole-cell patch-clamp recording, α-asarone inhibited spontaneous firing of output neurons, mitral cells (MCs), in mouse olfactory bulb brain slice preparation and hyperpolarized the membrane potential of MCs. The inhibitory effect of α-asarone persisted in the presence of ionotropic glutamate receptor blockers but was eliminated after adding a GABAA receptor blocker, suggesting that GABAA receptors mediated the inhibition of MCs by α-asarone. This hypothesis was supported by the finding that α-asarone evoked an outward current, but did not influence inhibitory postsynaptic currents (IPSCs). In addition to inhibiting spontaneous firing, α-asarone also inhibited the Nav1.2 channel, a dominant rat brain Na(+) channel subtype. The effects of α-asarone on a defined Nav1.2 were characterized using transfected cells that stably expressed the Nav1.2 channel isoform. α-Asarone displayed strong tonic inhibition of Nav1.2 currents in a concentration- and membrane potential-dependent fashion. α-Asarone reduced channel availability in steady-state inactivation protocols by enhancing or stabilizing Na(+) channel inactivation. Both Na(+) channel blockade and activation of GABAA receptors provide a possible mechanism for the known anti-epileptic effects of α-asarone. It also suggests that α-asarone could benefit patients with cough possibly through inhibiting a Na(+) channel subtype to inhibit peripheral and/or central sensitization of cough reflexes.