Cholinergic Activity Research Articles

Moving Beyond Amyloid in Alzheimer's Therapeutics

Moving Beyond Amyloid in Alzheimer's Therapeutics

Evaluation of Flurbiprofen's anticonvulsant properties in pilocarpine-induced convulsions in mice

Background: Flurbiprofen is a nonsteroidal anti-inflammatory drug, it has non-selective COX inhibition properties, some NSAIDS has an anticonvulsant effect and benefit as an analgesic in seizure patient.
 Objective: we aimed to evaluate the possible anticonvulsant effect of flurbiprofen in mice.
 Methods: We used 25 mature male mice for our study, the mice were divided into five groups, then to prevent peripheral cholinergic activation, mice in all groups were injected intraperitoneally with atropine sulphate (1 mg/kg) subcutaneously one hour after dosing. Seizures were induced ten minutes later with a 300 mg/kg i.p. injection of pilocarpine. After the pilocarpine injection, the animals were monitored for 1 hour. seizures severity was tested by the Racine scale.
 Results: flurbiprofen at 0, 10, 20 and 40 mg/kg orally causes a significant decrease in the onset of convulsion and a considerable decrease in the duration of convulsion in comparison with the control group. Flurbiprofen at 20 and 40 mg/kg orally inhibited seizure scores in pilocarpine-treated mice in a dose-dependent manner. High-dose of flurbiprofen (40 mg/kg) significantly reduced seizure scores, similar to diazepam.
 Conclusion: flurbiprofen has potential anticonvulsant properties in mice models, further study must be conducted to assess the primary mechanism of action.

The cholinergic basal forebrain provides a parallel channel for state-dependent sensory signaling to auditory cortex.

Cholinergic basal forebrain (CBF) signaling exhibits multiple timescales of activity with classic slow signals related to brain and behavioral states and fast, phasic signals reflecting behavioral events, including movement, reinforcement and sensory-evoked responses. However, it remains unknown whether sensory cholinergic signals target the sensory cortex and how they relate to local functional topography. Here we used simultaneous two-channel, two-photon imaging of CBF axons and auditory cortical neurons to reveal that CBF axons send a robust, nonhabituating and stimulus-specific sensory signal to the auditory cortex. Individual axon segments exhibited heterogeneous but stable tuning to auditory stimuli allowing stimulus identity to be decoded from population activity. However, CBF axons displayed no tonotopy and their frequency tuning was uncoupled from that of nearby cortical neurons. Chemogenetic suppression revealed the auditory thalamus as a major source of auditory information to the CBF. Finally, slow fluctuations in cholinergic activity modulated the fast, sensory-evoked signals in the same axons, suggesting that a multiplexed combination of fast and slow signals is projected from the CBF to the auditory cortex. Taken together, our work demonstrates a noncanonical function of the CBF as a parallel channel for state-dependent sensory signaling to the sensory cortex that provides repeated representations of a broad range of sound stimuli at all points on the tonotopic map.

Morus alba fruit diet ameliorates cognitive deficit in mouse model of streptozotocin-induced memory impairment.

Mounting evidence shows that dietary intake of fruits with polyphenols is beneficial to improve impaired memory functions. This study explored the preventive as well as therapeutic effects of diet enriched with Morus alba fruits extract (DEMA) in streptozotocin (STZ) induced mouse model of memory impairment. The study consisted of two facets: one aspect consisted of pretreatment of animals with DEMA for two weeks followed by STZ (i.c.v) intervention and the second phase involved induction of dementia with STZ (i.c.v) followed by treatment with DEMA for 14days. Cognitive functions of animals were measured by Morris Water Maze test and to delineate the associated mechanism of action, brain biochemical estimations (acetyl-cholinesterase activity, myeloperoxidase activity, thiobarbituric acid reactive species, superoxide dismutase activity, reduced glutathione and nitrite/nitrate) and histopathological studies (haematoxylin and eosin staining) were performed. Pre- and post- treatment with DEMA significantly prevented and attenuated, respectively, the detrimental effects of STZ on mice brain. The results demonstrated that dietary modification, by incorporation of M. alba fruits, reduces the incidence and aids in treatment of memory disorder in mice by reducing central cholinergic activity, decreasing oxidative stress and preventing neurodegeneration.

Evaluation of the anticonvulsant properties of flurbiprofen in pilocarpine-induced convulsions in mice

Background and objective: Flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), possesses non-selective COX inhibition properties. Some NSAIDs exhibit anticonvulsant effects and provide analgesic benefits for seizure patients. This study aimed to assess the potential anticonvulsant action of flurbiprofen in mice. Methods: Twenty-five mature male mice were divided into five groups for the study. To prevent peripheral cholinergic activation, mice in each group were injected intraperitoneally with atropine sulfate (1 mg/kg) subcutaneously one hour after dosing. Seizures were induced ten minutes later using an intraperitoneal injection of 300 mg/kg of pilocarpine. Following pilocarpine injection, the animals were monitored for 1 hour. Seizure severity was assessed using the Racine scale. Results: Oral administration of flurbiprofen at doses of 0, 10, 20, and 40 mg/kg resulted in a significant decrease in convulsion onset and a substantial reduction in convulsion duration compared to the control group. Flurbiprofen at 20 and 40 mg/kg inhibited seizure scores in pilocarpine-injected mice in a dose-dependent manner. A high dose of flurbiprofen (40 mg/kg) significantly reduced the duration of convulsions, delayed convulsion onset, and decreased seizure scores in mice (p <0.05). Conclusions: Flurbiprofen exhibits significant dose-dependent anticonvulsant activity. Further studies are necessary to determine the primary mechanism of action.

Neuroprotective effect of tangeretin against chromium-induced acute brain injury in rats: targeting Nrf2 signaling pathway, inflammatory mediators, and apoptosis

Potassium dichromate (PD) is an environmental xenobiotic commonly recognized as teratogenic, carcinogenic, and mutagenic in animals and humans. The present study was conducted to investigate the role of tangeretin (TNG) as a neuro-protective drug against PD-induced brain injury in rats. Thirty-two male adult Wistar rats were blindly divided into four groups (8 rats/group). The first group received saline intranasally (i.n.). The second group received a single dose of PD (2 mg/kg, i.n.). The third group received TNG (50 mg/kg; orally), for 14 days followed by i.n. of PD on the last day of the experiment. The fourth group received TNG (100 mg/kg; orally) for 14 days followed by i.n. of PD on the last day of the experiment. Behavioral indices were evaluated 18 h after PD administration. Neuro-biochemical indices and histopathological studies were evaluated 24 h after PD administration. Results of the present study revealed that rats intoxicated with PD induced- oxidative stress and inflammation via an increase in malondialdehyde (MDA) and a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and glutathione(GSH) levels with an increase in brain contents of tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6). Pre-treatment with TNG (100 mg/kg; orally) ameliorated behavior, cholinergic activities, and oxidative stress and decreased the elevated levels of pro-inflammatory mediators; TNF-α and IL-6 with a decrease in brain content of chromium residues detected by Plasma–Optical Emission Spectrometer. Also, the histopathological picture of the brain was improved significantly in rats that received TNG (100 mg/kg). Additionally, TNG decreased caspase-3 expression in the brain of PD rats. In conclusion, TNG possesses a significant neuroprotective role against PD-induced acute brain injury via modulating the Nrf2 signaling pathway and quenching the release of inflammatory mediators and apoptosis in rats.Graphical abstract

Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice.

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-β 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.

Steady-state and transient effects of SK channel block and adrenergic stimulation to counteract acetylcholine-induced arrhythmogenic effects in the human atria: A computational study

Hyperactivity of the parasympathetic nervous system has been linked to the development of paroxysmal atrial fibrillation (AF). The parasympathetic neurotransmitter acetylcholine (ACh) causes a reduction in action potential (AP) duration (APD) and an increase in resting membrane potential (RMP), both of which contribute to enhance the risk for reentry. Research suggests that small-conductance calcium activated potassium (SK) channels may be an effective target for treating AF. Therapies targeting the autonomic nervous system, either alone or in combination with other drugs, have been explored and have been shown to decrease the incidence of atrial arrhythmias. This study uses computational modeling and simulation to examine the impact of SK channel block (SKb) and β-adrenergic stimulation through Isoproterenol (Iso) on countering the negative effects of cholinergic activity in human atrial cell and 2D tissue models. The steady-state effects of Iso and/or SKb on AP shape, APD at 90% repolarization (APD90) and RMP were evaluated. The ability to terminate stable rotational activity in cholinergically-stimulated 2D tissue models of AF was also investigated. A range of SKb and Iso application kinetics, which reflect varying drug binding rates, were taken into consideration. The results showed that SKb alone prolonged APD90 and was able to stop sustained rotors in the presence of ACh concentrations up to 0.01 μM. Iso terminated rotors under all tested ACh concentrations, but resulted in highly-variable steady-state outcomes depending on baseline AP morphology. Importantly, the combination of SKb and Iso resulted in greater APD90 prolongation and showed promising anti-arrhythmic potential by stopping stable rotors and preventing re-inducibility.

Persistent Firing in Hippocampal CA1 Pyramidal Cells in Young and Aged Rats.

Persistent neuronal firing is often observed in working memory and temporal association tasks both in humans and animals, and is believed to retain necessary information in these tasks. We have reported that hippocampal CA1 pyramidal cells are able to support persistent firing through intrinsic mechanisms in the presence of cholinergic agonists. However, it still remains largely unknown how persistent firing is affected by the development of animals and aging. Using in vitro patch-clamp recordings from CA1 pyramidal cells in rat brain slices, we first show that the cellular excitability of these aged rats was significantly lower than the young rats, responding with fewer spikes to current injection. In addition, we found age-dependent modulations of input resistance, membrane capacitance, and spike width. However, persistent firing in aged (~2 years old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. In addition, spike after-hyperpolarization potential (AHP), was not increased by aging and did not correlate with the strength of persistent firing. Lastly, we estimated the depolarization current induced by the cholinergic activation. This current was proportional to the increased membrane capacitance of the aged group and was inversely correlated with the intrinsic excitability of cells. These observations indicate that robust persistent firing can be maintained in aged rats despite reduced excitability, due to the increased amount of cholinergically induced positive current.Significant statement:In an aging society, it is crucial to understand neural mechanisms underlying age-dependent cognitive impairments. In recent years, the importance of intrinsic cellular properties in cognitive functions such as memory has increasingly been recognized. However, research examining age-dependent alteration of intrinsic cellular mechanisms of persistent firing, which is believed to support working memory function, has so far been very scarce. In this study, we demonstrate that the ability to support persistent firing is kept intact in neurons from old rats, despite changes in other properties such as intrinsic excitability. These results identify the ability to support persistent firing as one potential cellular mechanism of rescued cognitive functions under cholinergic enhancement used in Alzheimer's disease and other dementias.

Selective activation of cholinergic neurotransmission from the medial septal nucleus to hippocampal pyramidal neurones improves sepsis-induced cognitive deficits in mice

BackgroundSepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections. MethodLipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-μm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP. ResultsIntracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml−1 to 382 [14] pg ml−1; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice. ConclusionsSystemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.

The sodium glucose co-transporter 2 inhibitor ertugliflozin for Alzheimer's disease: Inhibition of brain insulin signaling disruption-induced tau hyperphosphorylation

An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7–8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1Ser307/Total.IRS-1 ratio and increased Phospho.AktSer473/Total.Akt and Phospho.GSK3βSer9/Total.GSK3β ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.

Neuroprotective Effect of Methanolic Ajwa Seed Extract on Lipopolysaccharide-Induced Memory Dysfunction and Neuroinflammation: In Vivo, Molecular Docking and Dynamics Studies.

Islamic literature has indicated that daily consumption of Ajwa dates heals a variety of chronic diseases and disorders. The current research investigates the neuroprotective effect of methanolic Ajwa seed extract (MASE) on lipopolysaccharide (LPS)-induced cognitive deficits using multiple approaches. For animal studies, MASE (200 and 400 mg/kg, p.o.) was administrated for thirty consecutive days, and four doses of LPS (250 µg/kg, i.p.) were injected to induce neurotoxicity. Memory functions were evaluated using elevated plus-maze and novel object recognition tests. Acetylcholine (ACh) and neuroinflammatory markers (cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-β1) were estimated in brain tissues. Studies of molecular docking and dynamics were conducted to provide insight into the molecular-level mechanisms. MASE administration resulted in a significant reversal of LPS-induced memory impairment in both maze models. Both doses of MASE elevated the ACh levels in an LPS-treated rat brain. In addition, the extract lowered COX-2 and proinflammatory cytokines (TNF-α and IL-6) while increasing anti-inflammatory cytokines (IL-10 and TGF-β1) in LPS-treated brain tissues. Molecular modeling results revealed that the compound's ellagic acid, epicatechin, catechin, kaempferol, quercetin, and apigenin have the potential to act as a dual inhibitor of acetylcholinesterase (AChE) and COX-2 and can be responsible for the improvement of both cholinergic and inflammatory conditions, while the cinnamic acid, hesperidin, hesperetin, narengin, and rutin compounds are responsible only for the improvement of cholinergic transmission. The above compounds acted by interacting with the key residues Trp84, Asp72, Gly118, Ser200, Tyr334, and His440, which are responsible for the hydrolysis of ACh in AChE, while the COX-2 is inhibited by interacting with the residues (Val349, Leu352, Tyr355, Tyr385, Ala527, Ser530, and Leu531) of the hydrophobic channel. By promoting cholinergic activity and protecting neuroinflammation in the rat brain, MASE provides neuroprotection against LPS-induced cognitive deficits. Our preliminary findings will help with further drug discovery processes related to neuroinflammation-related neurodegeneration.

EEG Entropy in REM Sleep as a Physiologic Biomarker in Early Clinical Stages of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with EEG changes across the sleep-wake cycle. As the brain is a non-linear system, non-linear EEG features across behavioral states may provide an informative physiologic biomarker of AD. Multiscale fluctuation dispersion entropy (MFDE) provides a sensitive non-linear measure of EEG information content across a range of biologically relevant time-scales. To evaluate MFDE in awake and sleep EEGs as a potential biomarker for AD. We analyzed overnight scalp EEGs from 35 cognitively normal healthy controls, 23 participants with mild cognitive impairment (MCI), and 19 participants with mild dementia due to AD. We examined measures of entropy in wake and sleep states, including a slow-to-fast-activity ratio of entropy (SFAR-entropy). We compared SFAR-entropy to linear EEG measures including a slow-to-fast-activity ratio of power spectral density (SFAR-PSD) and relative alpha power, as well as to cognitive function. SFAR-entropy differentiated dementia from MCI and controls. This effect was greatest in REM sleep, a state associated with high cholinergic activity. Differentiation was evident in the whole brain EEG and was most prominent in temporal and occipital regions. Five minutes of REM sleep was sufficient to distinguish dementia from MCI and controls. Higher SFAR-entropy during REM sleep was associated with worse performance on the Montreal Cognitive Assessment. Classifiers based on REM sleep SFAR-entropy distinguished dementia from MCI and controls with high accuracy, and outperformed classifiers based on SFAR-PSD and relative alpha power. SFAR-entropy measured in REM sleep robustly discriminates dementia in AD from MCI and healthy controls.

Effect of Low- and High-Frequency Auricular Stimulation with Electro-Acupuncture on Cutaneous Microcirculation: A Cross-Over Study in Healthy Subjects

Background: The regulation of microcirculation depends on the dynamic interaction of different factors: the autonomic nervous system plays a pivotal role in the blood flow and acupuncture can modulate it, obtaining different results depending on the site, the frequency, and the intensity of the stimulation. Methods: 18 healthy subjects have been enrolled and have undergone two sessions of electroacupuncture stimulations: one session using high frequency and one with low frequency. Microcirculation has been monitored continuously during stimulation using the laser Doppler method. Results: The microcirculatory parameters have shown a significant difference between high and low-frequency stimulation, suggesting that low-frequency stimulation is more effective for obtaining a vasodilator effect. Discussion: Our results show that low-frequency stimulation can increase the cutaneous microcirculatory flux, without significantly modifying blood pressure and heart rate. The auricular stimulation causes an increase in the activity of the vagus nerve, increasing the cholinergic activity without acting on post-junctional muscarinic receptors. Conclusion: Auricular acupuncture has a significant impact on the regulation of microcirculation.

Promnesic, Anxiolytic and Antioxidant Effects of Glaucosciadium cordifolium (Boiss.) Burtt & Davis Essential Oil in a Zebrafish Model of Cognitive Impairment.

The purpose of this study was to investigate the effect of Glaucosciadium cordifolium essential oil (GCEO, 25 and 150 µL/L) on anxiety and learning and memory impairment induced by scopolamine (SCOP) in zebrafish. The chemical composition was analyzed by GC-MS, and the results showed that the highest content was limonene followed by α- and β-pinene, p-cymene and α-phellandrene. The dementia model was induced by SCOP (100 µM), whereas GCEO and galantamine (GAL, 1 mg/L) were delivered to the SCOP-induced model. It was found that GCEO significantly improved memory impairment and anxiety-like response induced by SCOP through the Y-maze, novel object recognition (NOR) test, and novel tank diving tests (NTT). Biochemical analyses showed that GCEO reduced SCOP-induced oxidative damage. Additionally, the cholinergic system activity was improved in the SCOP-induced model by decreasing the acetylcholinesterase (AChE) activity following the exposure to GCEO. It was clear that as a mixture, GCEO displays positive action in improving memory impairment through restoring cholinergic dysfunction and brain antioxidant status.

Not myopathic, but autonomic changes in patients with long-COVID syndrome: a case series

IntroductionNeurological sequelae following SARS-CoV-2 infection still represent a serious concern both for neurologists and neuroscientists. In our paper, we investigated pain, myalgia, and fatigue as symptoms in long-COVID patients with an electrophysiological approach, comprising the evaluation of sympathetic skin responses (SSRs) and quantitative electromyography (qEMG).Materials and methodsTwelve patients were enrolled (mean age, 47.7 ± 11.6 years), referred to our attention because of myalgia, pain, or muscle cramps, which persisted about 6 months after the diagnosis of SARS-CoV-2 infection. They underwent conventional electroneurography (ENG), needle electromyography (EMG), and SSRs; moreover, qEMG was performed by sampling at least 20 motor unit potentials (20–30 MUPs) during weak voluntary contraction in deltoid and tibialis anterior muscles. The mean duration, amplitude, and percentage of polyphasic potentials were assessed and compared with healthy and age-matched volunteers.ResultsENG did not disclose significant changes compared to healthy subjects; needle EMG did not reveal denervation activity. In addition, qEMG showed MUPs similar to those recorded in healthy volunteers in terms of polyphasia (deltoid: p = 0.24; TA: p = 0.35), MUP area (deltoid: p = 0.45; TA: p = 0.44), mean duration (deltoid: p = 0.06; TA: p = 0.45), and amplitude (deltoid: p = 0.27; TA: p = 0.63). SSRs were not recordable from lower limbs in seven patients (58%) and from the upper ones in three of them (25%).ConclusionOur data suggest an involvement of the autonomic system, with a focus on cholinergic efferent sympathetic activity, without any evidence of myopathic changes.

TaVNS Alleviates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Via Activating Basal Forebrain Cholinergic Neurons.

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30min per day) starting 24h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1+ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

Dose-Dependent Heart Rhythm Disturbance Occurring in Response to the Activation of Choline-Reactive Structures in Early Rat Ontogeny.

The effect of dose-dependent activation of cholinoreactive structures on the severity of sinus bradycardia occurring in some intact newborn rats during the first weeks after birth was analyzed in non-narcotized one-day-old (P1) and 16-day-old (P16) rats. The parameters of low-amplitude bradycardic oscillations of heart rhythm in norm and after administration of the acetylcholinesterase inhibitor physostigmine (eserine) in different doses (1/100, 1/10, and 3/4LD50) to rats were studied. The maximum increase in the power of low-amplitude brady-cardic oscillations was achieved during moderate activation of cholinoreactive structures after injection of eserine in a dose of 1/10LD50. Further increase in acetylcholine level led to disappearance of the sinus rhythm and development of pathological bradycardia. The data obtained indicate the immaturity of the mechanisms of heart rhythm regulation in rats immediately after birth. During activation of cholinoreactive structures, the severity of bradycardia oscillations increases exponentially at P1 and has an inverse exponential character at P16, which indicates a high risk of cardiac rhythmogenesis disorders and dysrhythmia development in newborn rats under conditions of excessive enhancement of cholinergic activation.

Increased Enzymatic Activity of Acetylcholinesterase Indicates the Severity of the Sterile Inflammation and Predicts Patient Outcome following Traumatic Injury.

Traumatic injury induces sterile inflammation, an immune response often associated with severe organ dysfunction. The cholinergic system acts as an anti-inflammatory in injured patients. Acetylcholinesterase (AChE), an enzyme responsible for the hydrolysis of acetylcholine, plays an essential role in controlling cholinergic activity. We hypothesized that a change in the AChE activity might indicate the severity of the traumatic injury. This study included 82 injured patients with an Injury Severity Score (ISS) of 4 or above and 40 individuals without injuries. Bedside-measured AChE was obtained on hospital arrival, followed by a second measurement 4-12 h later. C-reactive protein (CRP), white blood cell count (WBCC), and Sequential Organ Failure Assessment (SOFA) score were simultaneously collected. Injured patients showed an early and sustained increase in AChE activity. CRP remained unaffected at hospital admission and increased subsequently. Initially elevated WBCC recovered 4-12 h later. AChE activity directly correlated with the ISS and SOFA scores and predicted the length of ICU stay when measured at hospital admission. An early and sustained increase in AChE activity correlated with the injury severity and could predict the length of ICU stay in injured patients, rendering this assay a complementary diagnostic and prognostic tool at the hand of the attending clinician in the emergency unit.

Allergic inflammation disrupts epithelial electrogenic electrolyte transport through cholinergic regulation in the mouse colon.

Intestinal transport of electrolytes is regulated by the enteric nervous system. Acetylcholine (ACh) is considered the most important neurotransmitter for electrolyte transport in the colon. However, electrolyte transport regulated by ACh is not fully understood in the colon. We investigated the regulation of electrogenic electrolyte transport by cholinergic agonists in the mouse colon by measuring the short-circuit current (Isc) using an Ussing chamber system. Muscarinic stimulation induced transient electrogenic Cl- secretion, and nicotinic stimulation induced electrogenic K+ secretion to the apical side in the normal mouse colon, and these effects were reduced in the colon of mice with food allergy (FA). Administration of prednisolone to mice with FA suppressed mild inflammation in the colon and allergic symptoms and thereby ameliorated the disruption of electrogenic electrolyte transport induced not only by cholinergic pathway activation but also by electrical field stimulation and intracellular cAMP signaling pathway activation in the colon. These results suggest that the electrogenic electrolyte transport function in the colon is impaired by FA-induced colonic inflammation and that the suppression of inflammation ameliorates the dysfunction of electrogenic electrolyte transport in the colon of mice with FA.