Current concepts in treating mild cognitive impairment in Parkinson's disease.

Impairment in various aspects of cognition is recognized as an important non-motor symptom of Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) is common in non-demented PD patients and is often associated with severity of motor symptoms, disease duration and increasing age. Further, PD-MCI can have a significant negative effect on performance of daily life activities and may be a harbinger of development of PD dementia. Thus, there is significant interest in developing therapeutic strategies to ameliorate cognitive deficits in PD and improve cognitive functioning of PD patients. However, due to significant questions that remain regarding the pathophysiology of cognitive dysfunction in PD, remediation of cognitive dysfunction in PD has proven difficult. In this paper, we will focus on PD-MCI and will review some of the current therapeutic approaches being taken to try to improve cognitive functioning in patients with PD-MCI.

A randomized trial evaluating the safety profile of sugammadex in high surgical risk ASA physical class 3 or 4 participants.

BACKGROUND: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest. METHODS: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. RESULTS: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study. CONCLUSIONS: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346057 .

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

Acetylcholine-induced whealing in cholinergic urticaria - What does it tell us?

BACKGROUND: Cholinergic urticaria (CholU) is characterized by the occurrence of itchy wheals induced by sweating. Intradermal injections of acetylcholine (ACh) have been proposed to help with diagnosing CholU and subgrouping of patients, but controlled studies are largely missing. OBJECTIVE: To compare the rates of positive ACh test results in well characterized CholU patients and controls and to identify clinical features of CholU linked to ACh reactivity. METHODS: Acetylcholine was injected intradermally into 38 CholU patients and 73 matched healthy controls. Wheal and flare skin responses were assessed after 15 and 30 min and correlated with clinical features of CholU. RESULTS: At 15 min after intradermal injections of ACh, wheal and flare responses were significantly more frequent in CholU patients than healthy controls, wheals: 34 % vs.15% (P = 0.028); flares: 50 % vs.18 % (P <0.001). Also, wheals were 37 % and flares 172 % larger and of longer duration in CholU patients than in healthy controls (both P < 0.01). CholU patients with ACh-induced wheals (ACh+) had larger flare but not wheal responses in response to histamine than those without (ACh-; P = 0.011). Also, ACh-induced wheal responses were significantly correlated with sweating (r = 0.54, P = 0.046) in CholU patients. Finally, wheal responses lasted longer in ACh+ than in ACh- patients (P = 0.03). CONCLUSION: Intradermal ACh testing does not allow for the identification of CholU patients due to its low sensitivity. ACh-induced wheals, in patients with CholU, is linked to sweating and longer lasting symptoms. Intradermal ACh testing is an interesting tool for mechanistic studies in CholU.

Central cholinergic function and metabolic changes in streptozotocin-induced rat brain injury.

As glucose hypometabolism in the brain is an early sign of Alzheimer´s dementia (AD), the diabetogenic drug streptozotocin (STZ) has been used to induce Alzheimer-like pathology in rat brain by intracereboventricular injection (icv-STZ). However, many details of the pathological mechanism of STZ in this AD model remain unclear. Here, we report metabolic and cholinergic effects of icv-STZ using microdialysis in freely moving animals. We found that icv-STZ at a dose of 3 mg/kg (2 × 1.5 mg/kg) causes overt toxicity reflected in body weight loss. Three weeks after STZ administration, histological examination revealed a high number of glial fibrillary acidic protein reactive cells in the hippocampus, accompanied by Fluoro-Jade C-positive cells in the CA1 region. Glucose and lactate levels in microdialysates were unchanged, but mitochondrial respiration measured ex vivo was reduced by 9%-15%. High-affinity choline uptake, choline acetyltransferase, and acetylcholine esterase (AChE) activities in the hippocampus were reduced by 16%, 28%, and 30%, respectively. Importantly, extracellular acetylcholine (ACh) levels in the hippocampus were unchanged and responded to behavioral and pharmacological challenges. In comparison, extracellular ACh levels and cholinergic parameters in the striatum were unchanged or slightly increased. We conclude that the icv-STZ model poorly reflects central cholinergic dysfunction, an important characteristic of dementia. The icv-STZ model may be more aptly described as an animal model of hippocampal gliosis.

Cholinergic- rather than adrenergic-induced sweating play a role in developing and developed rat eccrine sweat glands.

Both cholinergic and adrenergic stimulation can induce sweat secretion in human eccrine sweat glands, but whether cholinergic and adrenergic stimulation play same roles in rat eccrine sweat glands is still controversial. To explore the innervations, and adrenergic- and cholinergic-induced secretory response in developing and developed rat eccrine sweat glands, rat hind footpads from embryonic day (E) 15.5-20.5, postanal day (P) 1-14, P21 and adult were fixed, embedded, sectioned and subjected to immunofluorescence staining for general fiber marker protein gene product 9.5 (PGP 9.5), adrenergic fiber marker tyrosine hydroxylase (TH) and cholinergic fiber marker vasoactive intestinal peptide (VIP), and cholinergic- and adrenergic-induced sweat secretion was detected at P1-P21 and adult rats by starch-iodine test. The results showed that eccrine sweat gland placodes of SD rats were first appeared at E19.5, and the expression of PGP 9.5 was detected surrounding the sweat gland placodes at E19.5, TH at P7, and VIP at P11. Pilocarpine-induced sweat secretion was first detected at P16 in hind footpads by starch-iodine test. There was no measurable sweating when stimulated by alpha- or beta-adrenergic agonists at all the examined time points. We conclude that rat eccrine sweat glands, just as human eccrine sweat glands, co-express adrenergic and cholinergic fibers, but different from human eccrine sweat glands, cholinergic- rather than adrenergic-induced sweating plays a role in the developing and developed rat eccrine sweat glands.

Integrated transcriptomic and proteomic analysis indicated that neurotoxicity of rats with chronic fluorosis may be in mechanism involved in the changed cholinergic pathway and oxidative stress.

BACKGROUND: To reveal the underling molecular mechanism in brain damage induced by chronic fluorosis, the neurotoxicity and its correlation were investigated by transcriptomics and proteomics. METHODS: Sprague-Dawley rats were treated with fluoride at different concentrations (0, 5, 50 and 100 ppm, prepared by NaF) for 3 months. Spatial learning and memory were evaluated by Morris water maze test; neuronal morphological change in the hippocampus was observed using Nissl staining; and the level of oxidative stress including reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by biological methods. The high-throughput transcriptome sequencing (RNA-Seq) and tandem mass tag (TMT) proteomic sequencing were performed to detect the expression of differentially expressed genes and proteins, respectively. RESULTS: The results showed that compared with control group, rats exposed to high-dose fluoride exhibited declined abilities of learning and memory, decreased SOD activity and increased ROS and MDA levels, with lighter colored Nissl bodies. A total of 28 important differentially expressed genes (DEGs) were screened out by transcriptomics. Then, functional enrichment analyses showed that upregulated proteins enriched in cellular transport, while downregulated proteins enriched in synapse-related pathways. Thirteen corresponding DEGs and DAPs (cor-DEGs-DAPs) were identified by differential expressions selected with positively correlated genes/proteins, most of which were related to neurodegenerative changes and oxidative stress response. CONCLUSION: These results provide new omics evidence that rats chronically exposed to high-dose fluoride can induce neurotoxicity in the brains through changes in the cholinergic pathway and oxidative stress.

Effect of short-term oral supplementation of crocin on age-related oxidative stress, cholinergic, and mitochondrial dysfunction in rat cerebral cortex.

BACKGROUND AND AIM: Aging is associated with oxidative stress and altered cholinergic and mitochondrial function. Crocin is a carotenoid antioxidant that quenches free radicals and protects cells and tissues from oxidation in biological systems. The aim of the present study is to investigate the effect of oral supplementation of Crocin on age-associated oxidative stress, cholinergic, and mitochondrial function in rat cerebral cortex. MAIN METHODS: The middle-aged (15 months old) rats were segregated into three groups (n = 6): Control (ad-libitum fed +0.9% saline as vehicle), Cro 50 (ad-libitum fed + crocin 50 mg/kg/day), Cro 150 (ad-libitum fed + crocin 150 mg/kg/day). The experiment was scheduled for 45 days. The serum and brain parameters were estimated after euthanasia. KEY FINDINGS: Crocin supplementation of Cro 50 and Cro 150 displayed a relative decline in body weight gain during the experimental period and significantly reduced age-associated serum triglyceride level over control. In rat cerebral cortex, age-associated macromolecular damage, decline in endogenous antioxidants and an increase in intracellular calcium concentration were significantly reversed due to oral supplementation of Crocin. Cro 150 significantly improved acetylcholine content as a consequence of acetylcholinesterase inhibition. Further, remarkable mitochondrial function was observed in Cro 150 over the control group as determined by citrate synthase and cytochrome C oxidase enzyme activities. SIGNIFICANCE: Oral supplementation of Crocin significantly reversed age-associated oxidative stress and neuroinflammatory markers. Meanwhile, Cro 150 remarkably improved cholinergic and mitochondrial function over the control group and facilitated further delay in the aging process due to enhanced cognitive effect.

Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer's disease.

The degeneration of cholinergic neurons is a prominent feature of Alzheimer's disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)-mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

T-495, a novel low cooperative M1 receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk.

M1 muscarinic acetylcholine receptor (M1 R) activation can be a new therapeutic approach for the treatment of cognitive deficits associated with cholinergic hypofunction. However, M1 R activation causes gastrointestinal (GI) side effects in animals. We previously found that an M1 R positive allosteric modulator (PAM) with lower cooperativity (α-value) has a limited impact on ileum contraction and can produce a wider margin between cognitive improvement and GI side effects. In fact, TAK-071, a novel M1 R PAM with low cooperativity (α-value of 199), improved scopolamine-induced cognitive deficits with a wider margin against GI side effects than a high cooperative M1 R PAM, T-662 (α-value of 1786), in rats. Here, we describe the pharmacological characteristics of a novel low cooperative M1 R PAM T-495 (α-value of 170), using the clinically tested higher cooperative M1 R PAM MK-7622 (α-value of 511) as a control. In rats, T-495 caused diarrhea at a 100-fold higher dose than that required for the improvement of scopolamine-induced memory deficits. Contrastingly, MK-7622 showed memory improvement and induction of diarrhea at an equal dose. Combination of T-495, but not of MK-7622, and donepezil at each sub-effective dose improved scopolamine-induced memory deficits. Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T α-synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T-495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y-maze task. Thus, low cooperative M1 R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction.

A Pilot Study of a Standardized Smoking Cessation Intervention for Patients with Vascular Disease.

BACKGROUND: The goal of this study is to evaluate the efficacy of a smoking cessation intervention performed by a vascular surgery provider compared with current smoking cessation practices. METHODS: Patients with peripheral arterial and aneurysmal disease who presented to the vascular surgery service at a tertiary care center over a 9-month period were randomized to either control or intervention group. Both control and intervention groups received 2 weeks of free nicotine patches and referral to an outpatient smoking-cessation program. The intervention group additionally received a brief presentation by a vascular surgeon regarding the benefits of smoking cessation, with a focus on vascular complications. At enrollment and at follow-up, patients underwent carbon monoxide breath testing and completed a survey. The primary outcome was smoking cessation or reduction among control and intervention groups in patients who underwent medical management, endovascular procedures, or open surgical procedures. Fisher's exact test was used to assess the primary outcome among groups. RESULTS: Fifty-nine patients were enrolled in the trial initially, but 55 had 1-month follow-up (control n = 28, intervention n = 27) and 52 had long-term follow-up (control n = 28, intervention n = 24). By long-term follow-up, 40 patients (77%) had reduced smoking by at least 50% and 16 patients (31%) had quit completely. At long-term follow-up, 88% of patients in the intervention group and 68% of patients in the control group reduced smoking (P = 0.1). CONCLUSIONS: A large proportion of vascular patients who received 2 weeks of nicotine replacement with or without the addition of brief smoking cessation counseling delivered by a vascular surgery provider were able to reduce smoking and maintain reduction after 6 months. Delivery of a brief standardized smoking cessation counseling session by a vascular surgery provider is safe and feasible. Additional randomized controlled trials with large enrollment periods and long follow-up are needed to determine the efficacy of this intervention in comparison to standard care.

Safflower (Carthamus tinctorius L.) seed attenuates memory impairment induced by scopolamine in mice via regulation of cholinergic dysfunction and oxidative stress.

Cholinergic dysfunction and oxidative stress are the most common causes of Alzheimer's disease (AD). Safflower seed contains various anti-oxidant and cholinergic improvement compounds, such as serotonin and its derivatives. In the present study, we investigated the protective effects and mechanisms of a safflower seed extract on scopolamine-induced memory impairment in a mouse model. The safflower seed extract was orally administered at a dose of 100 mg kg-1 day-1, and then behavior tests (such as T-maze and novel object recognition tests) were conducted. Acetyl cholinesterase (AChE) activity, reactive oxygen species (ROS) production, and antioxidant enzymes in the brain were measured. In behavior tests, the novel route exploration and object recognition were improved by the administration of the safflower seed extract, which suggests that the safflower seed extract improves memory function in the scopolamine-treated mouse model. In addition, the safflower seed extract-administered group showed inhibition of the AChE activity and improved cholinergic dysfunction. Furthermore, the administration of the safflower seed extract resulted in lower ROS production and higher antioxidant enzyme levels as compared to the scopolamine-treated group, suggesting the protective role of the safflower seed extract against oxidative stress. The results of the present study suggest that the safflower seed extract improves scopolamine-induced memory deficits via the inhibition of cholinergic dysfunction and oxidative stress. Therefore, safflower seeds might become a promising agent for memory improvement in AD patients.

Ameliorative Effects of Dendropanax morbifera on Cognitive Impairment Via Enhancing Cholinergic Functions and Brain-Derived Neurotrophic Factor Expression in ß-Amyloid-Induced Mice.

Alzheimer's disease accounts for the majority of dementia and shows hallmarks such as sequential cognitive dysfunction and abnormal behavior. Dendropanax morbifera (DM) has traditionally been used to treat a variety of diseases in East Asia. The aim of this study was to assess the therapeutic effects of DM on brain neuron damage and on cognitive deficit in neuronal cell induced by Aß1-42 in mice. Treatment with DM reduced the levels of intracellular reactive oxygen species and protected against the death of neuronal cells induced by Aß1-42 peptide. In addition, it was also found that pretreatment with DM decreased cognitive damage induced by Aß peptide via enhancing the cholinergic system and antioxidant defense system in mice. Furthermore, the study verified that the change in the expression of both cyclic-adenosine monophosphate response element binding protein and of brain-derived neurotrophic factor in the hippocampus in Aß peptide-treated mice was significantly ameliorated after treatment with DM. Accordingly, these results suggest that pretreatment with DM defends against oxidative stress and cognitive impairment caused by Aß peptide.

Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation.

BACKGROUND: Electrical vagal nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. This technique also remains under investigation as a specific treatment of patients with Alzheimer's disease. Recently we discovered that VNS induced hippocampal formation (HPC) type II theta rhythm, which is involved in memory consolidation. In the present study, we have extended our previous observation and addressed the neuronal substrate and pharmacological profile of HPC type II theta rhythm induced by VNS in anesthetized rats. METHODS: Male Wistar rats were implanted with a VNS cuff electrode around the left vagus nerve, a tungsten microelectrode for recording the HPC field activity, and a medial septal (MS) cannula for the injection of a local anesthetic, procaine, and muscarinic agents. A direct, brief effect of VNS on the HPC field potential was evaluated before and after medial-septal drug injection. RESULTS: Medial septal injection of local anesthetic, procaine, reversibly abolished VNS-induced HPC theta rhythm. With the use of cholinergic muscarinic agonist and antagonists, we demonstrated that medial septal M1 receptors are involved in the mediation of the VNS effect on HPC theta field potential. CONCLUSION: The MS cholinergic M1 receptor mechanism integrates not only central inputs from the brainstem synchronizing pathway, which underlies the production of HPC type II theta rhythm, but also the input from the vagal afferents in the brain stem.

Effects of prostaglandin-mediated and cholinergic-mediated miosis on morphology of the ciliary cleft region in dogs.

OBJECTIVE To compare morphology of the ciliary cleft (CC) region in dogs after topical administration of latanoprost, pilocarpine, or a combination of latanoprost and pilocarpine. ANIMALS 6 Beagles. PROCEDURES A prospective 4-phase crossover study with washout periods was performed. Latanoprost (phase L), pilocarpine (phase P), pilocarpine followed by latanoprost (phase PL), and latanoprost followed by pilocarpine (phase LP) were administered to the right eye. Artificial tears were administered to the left eye (control eye). For each phase, pupil diameter and intraocular pressure (IOP) were measured and ultrasonographic biomicroscopy was performed 2 hours after topical treatment. Angle opening distance (AOD), ciliary cleft width (CCW), ciliary cleft length (CCL), and ciliary cleft area (CCA) were evaluated. RESULTS All treated eyes had marked miosis without significant differences in pupil diameter among phases. Significant IOP reductions were detected for all phases, except phase P. The AOD and CCA were significantly increased in all phases for treated eyes, compared with results for control eyes. The CCW was significantly increased in phases P, PL, and LP; CCL was significantly increased in phases PL and LP. Comparison of treated eyes among phases revealed that CCW differed significantly between phases L and P and between phases L and PL. CONCLUSIONS AND CLINICAL RELEVANCE Prostaglandin-mediated and cholinergic-mediated miosis caused variations in CC configurations. When latanoprost and pilocarpine were used in combination, the first drug administered determined the cleft morphology, which was not fully reversed by the second drug. The CC morphology did not fully explain IOP reductions.

Toxicokinetics of the neonicotinoid insecticide imidacloprid in rainbow trout (Oncorhynchus mykiss).

Studies were conducted to determine the distribution and elimination of imidacloprid (IMI) in rainbow trout. Animals were injected with a low (47.6 µg/kg), medium (117.5 µg/kg) or high (232.7 µg/kg) dose directly into the bloodstream and allowed to depurate. The fish were then sampled to characterize the loss of IMI from plasma and its appearance in expired water (all dose groups) and urine (medium dose only). In vitro biotransformation of IMI was evaluated using trout liver S9 fractions. Mean total clearance (CLT) values determined by non-compartmental analysis of plasma time-course data were 21.8, 27.0 and 19.5 mL/h/kg for the low, medium and high dose groups, respectively. Estimated half-lives for the same groups were 67.0, 68.4 and 68.1 h, while fitted values for the steady-state volume of distribution (VSS) were 1.72, 2.23 and 1.81 L/kg. Branchial elimination rates were much lower than expected, suggesting that IMI is highly bound in blood. Renal clearance rates were greater than measured rates of branchial clearance (60% of CLT in the medium dose group), possibly indicating a role for renal membrane transporters. There was no evidence for hepatic biotransformation of IMI. Collectively, these findings suggest that IMI would accumulate in trout in continuous waterborne exposures.

Nicotine induces TIPE2 upregulation and Stat3 phosphorylation contributes to cholinergic anti-inflammatory effect.

Cholinergic anti-inflammatory pathway has therapeutic effect on inflammation-associated diseases. However, the exact mechanism of nicotine-mediated anti-inflammatory effect is still unclear. TIPE2, a new member of tumor necrosis factor-α-induced protein-8 family, is a negative regulator of immune homeostasis. However, the roles of TIPE2 in cholinergic anti-inflammatory effect are still uncertain. Here, we demonstrated that nicotine exerts its anti-inflammatory effect by TIPE2 upregulation and phosphorylated stat3 mediated the inhibition of NF-κB activation, which was supported by the following evidence: firstly, both nicotine and TIPE2 inhibit pro-inflammatory cytokine release via NF-κB inactivation. Secondly, nicotine upregulates TIPE2 expression via α7 nicotinic acetylcholine receptor. Moreover, the enhancement of stat3 phosphorylation and decrease of LPS-induced p65 translocation were achieved by nicotine treatment. Importantly, nicotine treatment augments the interaction of phosphorylated stat3 and p65, indicating that the inhibitory effect of nicotine on NF-κB activation was mediated with protein-protein interactions. Hence, this study revealed that TIPE2 upregulation and stat3 phosphorylation contribute to nicotine-mediated anti-inflammation effect, indicating that TIPE2 and stat3 might be potential molecules for dealing with inflammation-associated diseases.

Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function.

Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium-induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats.

Echinacoside ameliorates the memory impairment and cholinergic deficit induced by amyloid beta peptides via the inhibition of amyloid deposition and toxicology.

Echinacoside is a phenylethanoid glycoside and possesses neuroprotective activity in vitro and in vivo. This study investigates the role of the amyloid cascade and central neuronal function on the protective effects of echinacoside in amyloid ß peptide 1-42 (Aß 1-42)-treated SH-SY5Y cells and an Aß 1-42-infused rat. Echinacoside inhibited Aß 1-42 oligomerization in vitro and restored the cell viability that was reduced by Aß 1-42 in SH-SY5Y cells. Intracisternal infusion with Aß 1-42 by an osmotic pump caused cognitive deficits, an increase in amyloid deposition and acetylcholinesterase activities, and a decrease in the brain's levels of acetylcholine and dopamine. Echinacoside reduced the cognitive deficits and amyloid deposition, and it reversed the cortical cholinergic dysfunction that was caused by Aß 1-42 in rats. Echinacoside further reversed the memory impairment in the Morris water maze task caused by scopolamine in mice. Therefore, we suggest that echinacoside ameliorated cognitive dysfunction that was caused by Aß 1-42 by blocking amyloid deposition via inhibiting amyloid oligomerization and reversing the cortical cholinergic neuronal function via decreasing amyloid neurotoxicity.

Optogenetic excitation of cholinergic inputs to hippocampus primes future contextual fear associations.

Learning about context is essential for appropriate behavioral strategies, but important contingencies may not arise during initial learning. A variant of contextual fear conditioning, context pre-exposure facilitation, allows us to directly test the relationship between novelty-induced acetylcholine release and later contextual associability. We demonstrate that optogenetically-enhanced acetylcholine during initial contextual exploration leads to stronger fear after subsequent pairing with shock, suggesting that novelty-induced acetylcholine release primes future contextual associations.