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Alzheimer’s disease is the most common cause of dementia worldwide. As the disease course progresses, it can be debilitating to the patient and provide a large burden for their families and caregivers alike. As our population ages, it more important than ever to find safe and efficacious strategies to combat the cognitive effects of Alzheimer’s disease. While there have been many recent advances surrounding early identification of the disease including the use of PET imaging with specific targeted ligands or CSF analysis for biomarkers, there has been less progress in the development of disease modifying therapies to halt or reverse the symptoms. Vagus nerve stimulation has been a standard in therapy for drug-resistant epilepsy and depression for many years. It has been proven to be effective and has led to drastic improvement in many patients’ lives whose diseases were refractory to standard medications. There is evidence that stimulation of the vagal nerve leads to a physiologic response that also supports long term potentiation of memory within the hippocampus, though trials have been limited by sample size in the past due to the necessity of surgical implantation of the vagal nerve stimulator device. The recent development of non- invasive vagal nerve stimulation removes this limitation. This non-invasive strategy takes advantage of the auricular branch of the vagus nerve innervation of the ear to access the vagal pathway. The following work includes a proposal for a randomized control study to investigate the cognitive benefits of non-invasive vagal nerve stimulation of the auricular branch of the vagus nerve in a cohort of patients with MCI due to Alzheimer’s disease. This trial is planned for patients of neurology or gerontology practices associated with Boston Medical Center, Massachusetts General Hospital, Beth Israel Hospital, and Brigham and Women’s Hospital. Outcomes of this study will be the change in Mini- Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) score over a two-year intervention time.

Cardiovascular disease (CVD) is the leading cause of death worldwide and is expected to increase in prevalence. As a result of the individual and systemic healthcare impacts of CVD, heart failure, and its subsets, focusing on the alleviation of cardiac dysfunction and restoration of autonomic imbalance is paramount. Most research regarding cardiovascular disease is focused on mitigating heart failure from a cardiovascular perspective. However, this review will investigate heart failure from a neuroscientific perspective, highlighting the influence of the renin-angiotensin-aldosterone system, autonomic imbalance, and neuroinflammation on the progression of heart failure. By doing so, this research will bring light to how neuroscience may be applied to the cardiovascular system, and how interventions, such as vagal nerve stimulation, may be an untapped resource in mitigating the progression of heart failure. This review examined current relevant research to understand the brain regions implicated in the progression of heart failure, and to better understand how the nervous system may be modulated to improve heart failure outcomes through vagal nerve stimulation. This review sets the conceptual framework for future research to examine the structural changes observed in research animals who receive vagal nerve stimulation.

Heart failure is a prevalent health concern within the western world. It has huge economic, financial and personal implications. Despite the development of several clinically available treatments, heart failure associated mortality remains high. Heart failure patients display with dysfunction of the autonomic nervous system, including a high degree of vagal withdrawal. Consequently, the up-regulation of cardiac vagal tone, using vagal nerve stimulation (VNS) has recently gained attention as a potential new therapeutic approach to the treatment of heart failure. Clinical trials of VNS have produced mixed outcomes and very little is known about the mechanisms mediating the cardioprotective effects of VNS. This study has therefore implemented VNS in an ovine tachypaced model of heart failure, with the primary aim of quantifying its therapeutic effect in this model. Secondly, two potential underlying mechanisms of VNS have been investigated: 1) the effects of VNS on cellular calcium handling and 2) the effects of VNS on myocardial S-nitrosylation (S•NO).VNS treatment in this model of heart failure had a modest therapeutic effect. However, no differences in echocardiographic parameters, including those used as outcome measures in ongoing clinical trials, were observed between treated and untreated animals. Similarly, no differences in calcium handling parameters were observed between ventricular myocytes isolated from treated and untreated animals. Finally, VNS caused an increase in S•NO of several identified myocardial proteins when compared to untreated heart failure controls. However, this was a relatively small change compared to that observed between control and heart failure tissues. This data, as with studies before, highlights the need for a greater understanding of autonomic regulation and VNS in the heart failure setting, so that treatment strategies can be more effectively optimised. Given the limited therapeutic effect observed in this study, these potential mechanisms cannot be excluded as contributing to the cardioprotective effects of VNS observed in other studies.

Transcutaneous auricular vagal nerve stimulation (taVNS) is a non-invasive method of activating axons in the auricular branch of the vagus nerve through the concha of the outer ear. taVNS is under investigation as an alternative treatment option for a wide range of disorders. Vagal afferent fibers terminate in the nucleus of the solitary tract (NTS) where information is processed and relayed to higher brain regions influencing sympathetic and parasympathetic systems. Due to extensive neuronal connections, it is likely that taVNS could serve as a treatment option for many disorders, specifically cardiac, migraine, and gastric motility disorders. Human fMRI studies have indicated that taVNS elicits neuronal responses within NTS and spinal trigeminal nucleus (Sp5c). Studies have indicated that caudal NTS (cNTS) has substantial connections with the cardiac system, rostral NTS (rNTS) is relevant for gastric motility, and Sp5c is likely involved in migraine disorders due to meningeal connections. Aberrant neuronal signaling is likely responsible for the development of these disorders, and taVNS has the potential to modulate neuronal activity to reestablish homeostatic signaling. In this study, electrophysiological methods were used to interrogate neuronal activity of 50-70 neurons within cNTS, rNTS, and Sp5c following taVNS. A high-impedance tungsten electrode was placed stereotaxically in 15 male Sprague-Dawley rats anesthetized with chloralose. Changes in neuronal firing rates were investigated during and immediately following taVNS by comparing changes in neuronal activity to baseline levels using the software Spike 2 v9.14. Neurons were classified as negative responders if activity decreased more than 20%, positive responders if activity increased more than 20%, or non-responders if activity changes were less than 20%. Six different taVNS parameters were investigated using three frequencies (20, 100, 250Hz) at two intensity levels (0.5, 1.0mA). Data from this study suggest that taVNS can modulate neuronal activity in a frequency and intensity-dependent manner. The greatest positive activation for all 3 brain regions occurred at 20Hz, 1.0mA stimulation where an average of 46% ± 9% neurons showed increased firing compared to 29% ± 2% positive responders for other paradigms. The greatest negative activation for all 3 regions occurred at 100Hz, regardless of intensity, where an average of 33% ± 1% neurons showed reduced firing compared to 15% ± 2% negative responders for remaining paradigms. Based on what is known about cardiac, migraine, and gastric motility disorders, it is likely that taVNS can be used to modulate activity in NTS and Sp5c to provide beneficial treatment options to patients. Specifically, using paradigms yielding decreased activity in Sp5c could improve migraine symptoms, and paradigms increasing activity in cNTS and rNTS could improve cardiac and gastric motility disorders, respectively.

The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the “cholinergic anti-inflammatory pathway”. Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

Indiana University-Purdue University Indianapolis (IUPUI) / This thesis describes a novel method to reversibly and safely block nerve conduction using a low frequency alternating current (LFAC) waveform at 1 Hz applied through a bipolar extrafascicular electrode. This work follows up on observations made on excised mammalian peripheral nerves and earthworm nerve cords. An in-situ electrophysiology setup was used to assess the LFAC waveform on propagating action potentials (APs) within the cervical vagus nerve in anaesthetized Sprague-Dawley rats (n = 12). Two sets of bipolar cuff or hook electrodes were applied unilaterally to the cervical vagus nerve, which was crushed rostral to the electrodes to exclude reflex effects on the animal. Pulse stimulation was applied to the rostral electrode, while the LFAC conditioning waveform was applied to the caudal electrode. The efferent volley, if unblocked, elicits acute bradycardia and hypotension. The degree of block of the vagal stimulation induced bradycardia was used as a biomarker. Block was assessed by the ability to reduce the bradycardic drive by monitoring the heart rate (HR) and blood pressure (BP) during LFAC alone, LFAC with vagal stimulation, and vagal stimulation alone. LFAC applied via a hook electrode (n = 7) achieved 86.6 +/- 11% block at current levels 95 +/- 38 uAp (current to peak). When applied via a cuff electrode (n = 5) 85.3 +/- 4.60% block was achieved using current levels of 110+/-65 uAp. Furthermore, LFAC was explored on larger vagal afferent fibers in larger human sized nerve bundles projecting to effects mediated by a reflex. The effectiveness of LFAC was assessed in an in-situ electrophysiological setup on the left cervical vagus in anaesthetized domestic swine (n = 5). Two bipolar cuff electrodes were applied unilaterally to the cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar extrafascicular cuff electrode was placed most rostral on the nerve for recording of propagating APs induced by electrical stimulation and blocked via the LFAC waveform. Standard pulse stimulation was applied to the left cervical vagus to induce the Hering-Breuer reflex. If unblocked, the activation of the Hering-Breuer reflex would cause breathing to slow down and potentially cease. Block was quantified by the ability to reduce the effect of the Hering-Breuer reflex by monitoring the breathing rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. LFAC achieved 87.2 +/- 8.8% (n = 5) block at current levels of 0.8 +/- 0.3 mAp. Compound nerve action potentials (CNAP) were monitored directly. They show changes in nerve activity during LFAC, which manifests itself as the slowing and amplitude reduction of components of the CNAPs. Since the waveform is balanced, all forward reactions are reversed, leading to a blocking method that is similar in nature to DC block without the potential issues of toxic byproduct production. These results suggest that LFAC can achieve a high degree of nerve block in both small and large nerve bundles, resulting in the change in behavior of a biomarker, in-vivo in the mammalian nervous system at low amplitudes of electrical stimulation that are within the water window of the electrode.

INTRODUÇÃO: A atuação do sistema nervoso parassimpático em células imunes é conhecida como \"Via Anti-inflamatória Colinérgica\". Trabalhos prévios demonstraram que a estimulação vagal reduz a inflamação e melhora a sobrevida em modelos experimentais com sepse. Neste estudo avaliamos se o uso do anticolinesterásico piridostigmina: altera o número de linfócitos T (CD4+ e CD8+) convencionais (CD25+Foxp3-) e reguladores (CD25+Foxp3+) no sangue periférico, no baço e no miocárdio; modifica a concentração de citocinas (interleucina 1, interleucina 6, TNFalfa) no miocárdio; e influencia a função ventricular após infarto agudo do miocárdio experimental (IAM) em ratos. MÉTODOS: Utilizamos ratos machos adultos da linhagem Wistar, com peso variando entre 200 e 250 g, divididos em 3 grupos de 20 animais cada: grupo controle (GC), grupo infartado sem tratamento (IC) e grupo infartado tratado com piridostigmina (IP). O infarto agudo do miocárdio (IAM) foi obtido com a técnica da ligadura da artéria coronária esquerda, e o grupo IP recebeu piridostigmina na dose de 40mg/kg/dia na água de beber, iniciada 4 dias antes do IAM. Todos os animais foram submetidos à canulação da artéria femoral no dia seguinte ao IAM para registro das curvas de pressão arterial, e posterior análise dos componentes da variabilidade da freqüência cardíaca (VFC), domínio do tempo (SDNN e RMSSD) e da freqüência (componentes LF e HF); o estudo ecocardiográfico foi realizado no segundo dia pós IAM. No terceiro dia pós IAM, os ratos foram divididos em subgrupos de 10 animais, e sacrificados de forma específica para coleta de materiais: 500 ul de sangue periférico e baço fresco para realização da técnica de citometria de fluxo; ventrículo esquerdo para dosagem de citocinas pela técnica de ELISA; e ventrículo esquerdo para realização de imunohistoquímica. Foram usadas as técnicas padronizadas e de uso corrente nos laboratórios. Os resultados foram avaliados por análise de variância (ANOVA) multifatorial, usando o programa GraphPad Prism com teste post hoc de Tukey. RESULTADOS: O grupo IC comparado ao grupo controle apresentou queda significativa da pressão arterial e aumento da freqüência cardíaca. O grupo IP, comparado ao grupo IC, apresentou maior atividade vagal, caracterizada pela significante redução da FC e aumento da VFC (SDNN, 9,2±1,5 vs 5,2±0,5 p < 0,05). Os parâmetros ecocardiográficos avaliados evidenciaram presença de área hipo/acinética e redução da fração de ejeção do ventrículo esquerdo nos grupos infartados, de igual magnitude. Com relação ao número de linfócitos T, verificamos que o grupo IC, comparado ao grupo controle, apresentou número significativamente menor de linfócitos reguladores (CD25+Foxp3+) no sangue periférico (CD4+: 63,5 ±1,4 vs 70,6 ±3,2%, e CD8+: 68,3 ±1,9 vs 76,1 ± 2,8%). O grupo IP, comparado ao grupo IC, apresentou significativa redução do número de linfócitos T convencionais no sangue periférico (respectivamente, CD4+: 1,5 ±0,2 vs 2,2 ± 0,2 %; CD8+: 1,1 ± 0,1 vs 1,8 ± 0,9%), e no baço houve redução somente do tipo CD4+ (respectivamente, 1,4 ± 0,2 vs 2,2 ± 0,2%), com aumento do tipo CD8+ (respectivamente, 1,2 ± 0,1 vs 0,7 ± 0,1 %). O grupo IP também apresentou significativo aumento de linfócitos reguladores (CD25+Foxp3+) no sangue periférico (respectivamente, CD4+: 76,5 ± 2,9 vs 63,5 ± 1,4 %; CD8+: 75,1 ± 1,0 vs 68,3 ± 1,9 %), e não apresentou diferenças significativas no número dessas células no baço. O grupo IC comparado ao grupo controle apresentou significativa marcação de anticorpos para CD4 e CD8 nas áreas infartada e peri-infarto por meio da análise de imunohistoquímica. O grupo IP comparado ao grupo IC, apresentou significativo aumento de CD4+ (respectivamente, 20,9 ± 6,5 vs 12,2 ± 2,5, p < 0,05) e de CD8+ (respectivamente, 17,9 ± 2,8 vs 5,8 ± 1,1%, p < 0,05) na área infartada; observamos redução significativa na marcação de CD4+ (respectivamente, 6,0 ±1,2 vs 12,5 ±4,8) na área peri-infarto, sem alterações significativas na marcação de CD8+. CONCLUSÃO: O tratamento com piridostigmina em ratos com IAM está associado a aumento da atividade vagal, aumento do número de linfócitos reguladores (CD25+Foxp3+) no sangue periférico e maior mobilização de células inflamatórias (CD4+ e CD8+) para a área infartada no miocárdio, com redução de CD4+ na área peri-infarto, no entanto sem mudança de CD8+ nesta região. A mudança do perfil inflamatório decorrente do aumento da atividade vagal na fase aguda do IAM, pode ser um possível mecanismo para explicar os benefícios detectados no remodelamento cardíaco após o IAM, em especial, na redução da área de lesão e na melhora da função ventricular, com uso de anticolinesterásicos / INTRODUTION: The role of the parasympathetic nervous system in immune cells is known as \"Cholinergic anti-inflammatory pathway\". In previous work has demonstrated that vagal stimulation reduces inflammation and improves survival in experimental sepsis models. The aim of the present study evalued the use of anticholinesterase pyridostigmine: change the number of T lymphocytes (CD4+ and CD8+) conventional (CD25+Foxp3-) and regulatory (CD25+Foxp3+) in peripheral blood, spleen, and myocardium: modifies the concentration of cytokines (interleukin-1, interleukin-6, TNFalfa) in the myocardium, and influences ventricular function after experimental myocardial infarction (MI) in rats. METHODS: Adult male rats of Wistar strain, weighing between 200 and 250 g were divided into 3 groups of 20 animals each: control group (GC); untreated group without treatment (IC) and infarcted group treated with pyridostigmine (IP). Acute myocardial infarction (AMI) was obtained with the technique of ligation of the left coronary artery, and the IP group received pyridostigmine dose of 40 mg/Kg/day in drinking water starting 4 days before the AMI. All animals underwent cannulation of the femoral artery on the day following AMI to record the blood pressure curves, and subsequent analysis of the components of heart rate variability (HRV), the time domain (SDNN and RMSSD) and frequency (components LF and HF), the echocardiografic study was performed on the second day after AMI. On the third day post-MI, mice were divided into subgroups of 10 animals, and were sacrificed in order to collet specific materials: 500 ul of fresh peripheral blood and spleen technique for performing flow cytometry left ventricle for measurement of cytokine ELISA, and the left ventricle to perform immunohistochemistry. Techniques used were standardized and commonly used in laboraties. The results were evaluated by analysis of variance (ANOVA) multifactorial, using the GraphPad Prism with Tukey post hoc test RESULTS: The HF group compared to the control group showed a significant drop in blood pressure and increased heart rate. The IP group compared to the IC group showed higher vagal activity, characterized by a significant reduction in HR and increase HVR (SDNN, 9.2 ± 1.5 vs 5.2 ± 0.5, p < 0.05). The echocardiography parameters evaluated showed presence of area hypo/acinetic and reduced ejection fraction of the left ventricle in infracted groups of equal magnitude. Regarding the number of T lymphocytes, we found that the IC group compared with the control group showed significantly fewer lymphocytes regulators (CD25+Foxp3+) in peripheral blood (CD4+:63.5 ± 1.4 vs 70.6 ± 3.2% and CD8+ cells: 68.3 ± 1.9 vs 76.1 ± 2.8%). The IP group compared to the IC group showed a significant reduction in the number of conventional T lymphocytes in peripheral blood (CD4+:1.5 ± 0.2 vs 2.2 ± 0.2%; CD8+: 1.1 ± 0.1 vs 1.8 ± 0.9%) and was reduced only in the spleen of the type CD4+(1.4 ± 0.2 vs 2.2 ± 0,2%) with increased CD8+(1.2 ± 0.1 vs 0.7 ± 0.1%). The IP group also showed a significant increase of lymphocytes regulators (CD25+Foxp3+) in peripheral blood (CD4+: 76.5 ± 2.9 vs 63.5 ± 1.4%; CD8+:75.1 ± 1.0 vs 68.3 ± 1.9%), and no significant differences in the number of these cells in the spleen. The IC group compared to the control group showed significant labeling antibodies to CD4 and CD8 areas infarcted and peri-infarction by immunohistochemical analysis. The IP group compared to the IC group showed a significant increase in CD4 (20.9 ± 6.5 vs 12.2 ± 2.5, p < 0.05) and CD8 (17.9 ± 2.8 vs 5.8 ± 1.1%, p < 0.05) in the infarcted area, and we observed a significant reduction in the labeling of CD4 (6.0 ± 1.2 vs 12.5± 4.8) in the peri-infraction without significant changes in the marking of CD8. CONCLUSION: The treatment with pyridostigmine in rats with acute myocardial infarction is associated with increased vagal activity, increased number of regulatory lymphocytes (CD25+Foxp3+) in peripheral blood and increased mobilization of inflammatory cells (CD4 and CD8) to the infarcted myocardium, with reduction of these cells in the peri-infarction. The change of the inflammatory profile due to increased vagal activity may be a possible mechanism to explain the benefits in the evolution of myocardial infarction, especially in the improvement of cardiac remodeling and maintenance of ventricular function with anticholinesterase drugs

INTRODUÇÃO: A atuação do sistema nervoso parassimpático em células imunes é conhecida como \"Via Anti-inflamatória Colinérgica\". Trabalhos prévios demonstraram que a estimulação vagal reduz a inflamação e melhora a sobrevida em modelos experimentais com sepse. Neste estudo avaliamos se o uso do anticolinesterásico piridostigmina: altera o número de linfócitos T (CD4+ e CD8+) convencionais (CD25+Foxp3-) e reguladores (CD25+Foxp3+) no sangue periférico, no baço e no miocárdio; modifica a concentração de citocinas (interleucina 1, interleucina 6, TNFalfa) no miocárdio; e influencia a função ventricular após infarto agudo do miocárdio experimental (IAM) em ratos. MÉTODOS: Utilizamos ratos machos adultos da linhagem Wistar, com peso variando entre 200 e 250 g, divididos em 3 grupos de 20 animais cada: grupo controle (GC), grupo infartado sem tratamento (IC) e grupo infartado tratado com piridostigmina (IP). O infarto agudo do miocárdio (IAM) foi obtido com a técnica da ligadura da artéria coronária esquerda, e o grupo IP recebeu piridostigmina na dose de 40mg/kg/dia na água de beber, iniciada 4 dias antes do IAM. Todos os animais foram submetidos à canulação da artéria femoral no dia seguinte ao IAM para registro das curvas de pressão arterial, e posterior análise dos componentes da variabilidade da freqüência cardíaca (VFC), domínio do tempo (SDNN e RMSSD) e da freqüência (componentes LF e HF); o estudo ecocardiográfico foi realizado no segundo dia pós IAM. No terceiro dia pós IAM, os ratos foram divididos em subgrupos de 10 animais, e sacrificados de forma específica para coleta de materiais: 500 ul de sangue periférico e baço fresco para realização da técnica de citometria de fluxo; ventrículo esquerdo para dosagem de citocinas pela técnica de ELISA; e ventrículo esquerdo para realização de imunohistoquímica. Foram usadas as técnicas padronizadas e de uso corrente nos laboratórios. Os resultados foram avaliados por análise de variância (ANOVA) multifatorial, usando o programa GraphPad Prism com teste post hoc de Tukey. RESULTADOS: O grupo IC comparado ao grupo controle apresentou queda significativa da pressão arterial e aumento da freqüência cardíaca. O grupo IP, comparado ao grupo IC, apresentou maior atividade vagal, caracterizada pela significante redução da FC e aumento da VFC (SDNN, 9,2±1,5 vs 5,2±0,5 p < 0,05). Os parâmetros ecocardiográficos avaliados evidenciaram presença de área hipo/acinética e redução da fração de ejeção do ventrículo esquerdo nos grupos infartados, de igual magnitude. Com relação ao número de linfócitos T, verificamos que o grupo IC, comparado ao grupo controle, apresentou número significativamente menor de linfócitos reguladores (CD25+Foxp3+) no sangue periférico (CD4+: 63,5 ±1,4 vs 70,6 ±3,2%, e CD8+: 68,3 ±1,9 vs 76,1 ± 2,8%). O grupo IP, comparado ao grupo IC, apresentou significativa redução do número de linfócitos T convencionais no sangue periférico (respectivamente, CD4+: 1,5 ±0,2 vs 2,2 ± 0,2 %; CD8+: 1,1 ± 0,1 vs 1,8 ± 0,9%), e no baço houve redução somente do tipo CD4+ (respectivamente, 1,4 ± 0,2 vs 2,2 ± 0,2%), com aumento do tipo CD8+ (respectivamente, 1,2 ± 0,1 vs 0,7 ± 0,1 %). O grupo IP também apresentou significativo aumento de linfócitos reguladores (CD25+Foxp3+) no sangue periférico (respectivamente, CD4+: 76,5 ± 2,9 vs 63,5 ± 1,4 %; CD8+: 75,1 ± 1,0 vs 68,3 ± 1,9 %), e não apresentou diferenças significativas no número dessas células no baço. O grupo IC comparado ao grupo controle apresentou significativa marcação de anticorpos para CD4 e CD8 nas áreas infartada e peri-infarto por meio da análise de imunohistoquímica. O grupo IP comparado ao grupo IC, apresentou significativo aumento de CD4+ (respectivamente, 20,9 ± 6,5 vs 12,2 ± 2,5, p < 0,05) e de CD8+ (respectivamente, 17,9 ± 2,8 vs 5,8 ± 1,1%, p < 0,05) na área infartada; observamos redução significativa na marcação de CD4+ (respectivamente, 6,0 ±1,2 vs 12,5 ±4,8) na área peri-infarto, sem alterações significativas na marcação de CD8+. CONCLUSÃO: O tratamento com piridostigmina em ratos com IAM está associado a aumento da atividade vagal, aumento do número de linfócitos reguladores (CD25+Foxp3+) no sangue periférico e maior mobilização de células inflamatórias (CD4+ e CD8+) para a área infartada no miocárdio, com redução de CD4+ na área peri-infarto, no entanto sem mudança de CD8+ nesta região. A mudança do perfil inflamatório decorrente do aumento da atividade vagal na fase aguda do IAM, pode ser um possível mecanismo para explicar os benefícios detectados no remodelamento cardíaco após o IAM, em especial, na redução da área de lesão e na melhora da função ventricular, com uso de anticolinesterásicos / INTRODUTION: The role of the parasympathetic nervous system in immune cells is known as \"Cholinergic anti-inflammatory pathway\". In previous work has demonstrated that vagal stimulation reduces inflammation and improves survival in experimental sepsis models. The aim of the present study evalued the use of anticholinesterase pyridostigmine: change the number of T lymphocytes (CD4+ and CD8+) conventional (CD25+Foxp3-) and regulatory (CD25+Foxp3+) in peripheral blood, spleen, and myocardium: modifies the concentration of cytokines (interleukin-1, interleukin-6, TNFalfa) in the myocardium, and influences ventricular function after experimental myocardial infarction (MI) in rats. METHODS: Adult male rats of Wistar strain, weighing between 200 and 250 g were divided into 3 groups of 20 animals each: control group (GC); untreated group without treatment (IC) and infarcted group treated with pyridostigmine (IP). Acute myocardial infarction (AMI) was obtained with the technique of ligation of the left coronary artery, and the IP group received pyridostigmine dose of 40 mg/Kg/day in drinking water starting 4 days before the AMI. All animals underwent cannulation of the femoral artery on the day following AMI to record the blood pressure curves, and subsequent analysis of the components of heart rate variability (HRV), the time domain (SDNN and RMSSD) and frequency (components LF and HF), the echocardiografic study was performed on the second day after AMI. On the third day post-MI, mice were divided into subgroups of 10 animals, and were sacrificed in order to collet specific materials: 500 ul of fresh peripheral blood and spleen technique for performing flow cytometry left ventricle for measurement of cytokine ELISA, and the left ventricle to perform immunohistochemistry. Techniques used were standardized and commonly used in laboraties. The results were evaluated by analysis of variance (ANOVA) multifactorial, using the GraphPad Prism with Tukey post hoc test RESULTS: The HF group compared to the control group showed a significant drop in blood pressure and increased heart rate. The IP group compared to the IC group showed higher vagal activity, characterized by a significant reduction in HR and increase HVR (SDNN, 9.2 ± 1.5 vs 5.2 ± 0.5, p < 0.05). The echocardiography parameters evaluated showed presence of area hypo/acinetic and reduced ejection fraction of the left ventricle in infracted groups of equal magnitude. Regarding the number of T lymphocytes, we found that the IC group compared with the control group showed significantly fewer lymphocytes regulators (CD25+Foxp3+) in peripheral blood (CD4+:63.5 ± 1.4 vs 70.6 ± 3.2% and CD8+ cells: 68.3 ± 1.9 vs 76.1 ± 2.8%). The IP group compared to the IC group showed a significant reduction in the number of conventional T lymphocytes in peripheral blood (CD4+:1.5 ± 0.2 vs 2.2 ± 0.2%; CD8+: 1.1 ± 0.1 vs 1.8 ± 0.9%) and was reduced only in the spleen of the type CD4+(1.4 ± 0.2 vs 2.2 ± 0,2%) with increased CD8+(1.2 ± 0.1 vs 0.7 ± 0.1%). The IP group also showed a significant increase of lymphocytes regulators (CD25+Foxp3+) in peripheral blood (CD4+: 76.5 ± 2.9 vs 63.5 ± 1.4%; CD8+:75.1 ± 1.0 vs 68.3 ± 1.9%), and no significant differences in the number of these cells in the spleen. The IC group compared to the control group showed significant labeling antibodies to CD4 and CD8 areas infarcted and peri-infarction by immunohistochemical analysis. The IP group compared to the IC group showed a significant increase in CD4 (20.9 ± 6.5 vs 12.2 ± 2.5, p < 0.05) and CD8 (17.9 ± 2.8 vs 5.8 ± 1.1%, p < 0.05) in the infarcted area, and we observed a significant reduction in the labeling of CD4 (6.0 ± 1.2 vs 12.5± 4.8) in the peri-infraction without significant changes in the marking of CD8. CONCLUSION: The treatment with pyridostigmine in rats with acute myocardial infarction is associated with increased vagal activity, increased number of regulatory lymphocytes (CD25+Foxp3+) in peripheral blood and increased mobilization of inflammatory cells (CD4 and CD8) to the infarcted myocardium, with reduction of these cells in the peri-infarction. The change of the inflammatory profile due to increased vagal activity may be a possible mechanism to explain the benefits in the evolution of myocardial infarction, especially in the improvement of cardiac remodeling and maintenance of ventricular function with anticholinesterase drugs