Neuroimmune interactions and kidney disease

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.

Effect of Placenta-Derived Mesenchymal Stem Cells in a Dementia Rat Model via Microglial Mediation: a Comparison between Stem Cell Transplant Methods

PURPOSE: Loss of cholinergic neurons in the hippocampus is a hallmark of many dementias. Administration of stem cells as a therapeutic intervention for patients is under active investigation, but the optimal stem cell type and transplantation modality has not yet been established. In this study, we studied the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyzed their mechanisms of therapeutic action. MATERIALS AND METHODS: Dementia modeling was established by intraventricular injection of 192 IgG-saporin, which causes lesion of cholinergic neurons. Sixty-five male Sprague-Dawley rats were divided into five groups: control, lesion, lesion+ICV injection of pMSCs, lesion+IV injection of pMSCs, and lesion+donepezil. Rats were subjected to the Morris water maze and subsequent immunostaining analyses. RESULTS: Both ICV and IV pMSC administrations allowed significant cognitive recovery compared to the lesioned rats. Acetylcholinesterase activity was significantly rescued in the hippocampus of rats injected with pMSCs post-lesion. Choline acetyltransferase did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Number of microglial cells increased in lesioned rats and significantly decreased back to normal levels with pMSC injection. CONCLUSION: Our results suggest that ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons.

New progress in study of inflammatory reflex / 中国病理生理杂志

Proinflammatory cytokines induced by peripheral immune challenge can activate the inflammatory reflex, which results in negative-feedback control of inflammation .Some recent studies revealed that it is the splanchnic nerve , not the vagus nerve , to constitute the efferent arm of the inflammatory reflex .Further researches are needed to iden-tify the neural construction and regulatory mechanism of the inflammatory reflex , which might be harnessed for the treatment of inflammation and the development of anti-inflammatory drugs .

Wogonin Attenuates Hippocampal Neuronal Loss and Cognitive Dysfunction in Trimethyltin-Intoxicated Rats

We examined whether wogonin (WO) improved hippocampal neuronal activity, behavioral alterations and cognitive impairment, in rats induced by administration of trimethyltin (TMT), an organotin compound that is neurotoxic to these animals. The ability of WO to improve cognitive efficacy in the TMT-induced neurodegenerative rats was investigated using a passive avoidance test, and the Morris water maze test, and using immunohistochemistry to detect components of the acetylcholinergic system, brain-derived neurotrophic factor (BDNF), and cAMP-response element-binding protein (CREB) expression. Rats injected with TMT showed impairments in learning and memory and daily administration of WO improved memory function, and reduced aggressive behavior. Administration of WO significantly alleviated the TMT-induced loss of cholinergic immunoreactivity and restored the hippocampal expression levels of BDNF and CREB proteins and their encoding mRNAs to normal levels. These findings suggest that WO might be useful as a new therapy for treatment of various neurodegenerative diseases.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Phellodendron amurense and Its Major Alkaloid Compound, Berberine Ameliorates Scopolamine-Induced Neuronal Impairment and Memory Dysfunction in Rats

We examine whether Phellodendron amurense (PA) and its major alkaloid compound, berberine (BER), improved memory defects caused by administering scopolamine in rats. Effects of PA and BER on the acetylcholinergic system and pro-inflammatory cytokines in the hippocampus were also investigated. Male rats were administered daily doses for 14 days of PA (100 and 200 mg/kg, i.p.) and BER (20 mg/kg, i.p.) 30 min before scopolamine injection (2 mg/kg, i.p.). Daily administration of PA and BER improved memory impairment as measured by the passive avoidance test and reduced the escape latency for finding the platform in the Morris water maze test. Administration of PA and BER significantly alleviated memory-associated decreases in cholinergic immunoreactivity and restored brain-derived neurotrophic factor and cAMP-response element-binding protein mRNA expression in the hippocampus. PA and BER also decreased significantly the expression of proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha and cyclooxygenase-2 mRNA in the hippocampus. These results demonstrated that PA and BER had significant neuroprotective effects against neuronal impairment and memory dysfunction caused by scopolamine in rats. These results suggest that PA and BER may be useful as therapeutic agents for improving cognitive functioning by stimulating cholinergic enzyme activity and alleviating inflammatory responses.

Effect of transplantation of the neural stem cells on the cholinergic neurons in hippocampus of vascular dementia rats / 中国康复理论与实践

@#ObjectiveTo study the change of cholinergic neurons of hippocampus of vascular dementia rats after transplantation of the neural stem cells(NSCs) in hippocampus.MethodsAfter the vascular dementia model was reproduced,the rats were randomly divided into transplantation,dementia and pseudo-operative groups.8 weeks after operation,immunofluorescence was used to observe the survivors and migration of neural stem cells.Immunochemistry staining was used to observe the number of ChAT positive neurons in hippocampus.ResultsThe number of the ChAT positive neurons in the CA1 subfield of the hippocampus were more significantly increased in transplantation group than that in dementia group. ConclusionChAT positive neurons can be found in hippocampus area of vascular dementia rats after transplanting NSCs into the hippocampus, which seem to be cholinergic neurons.

Effect of hyperbaric oxygen therapy on the cholinergic neurons of hippocampus and praxiology of vascular dementia rats / 中国康复理论与实践

@#ObjectiveTo study the effect of hyperbaric oxygen therapy on the cholinergic neurons of hippocampus and praxiology of vascular dementia rats.MethodsThe vascular dementia models were made and divided into control and therapy group. After 30 days of HBO therapy, abilities of learning and memory of rats were tested by using the Morris water maze. Immunochemistry staining was used to observe the number of cholinergic neurons of CA1 subfield of hippocampus. ResultsAbilities of learning and memory of rats and the number of the neurons positive to ChAT like immunoreaction in the CA1 subfield of the hippocampus significantly increased in therapy group.ConclusionHyperbaric oxygen therapy is effective on the vascular dementia model rats.

Muscarine M2 Receptor-mediated Presynaptic Inhibition of GABAergic Transmission in Rat Meynert Neurons

Cholinergic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) by the activation of muscarine receptors was investigated in mechanically dissociated rat nucleus basalis of the Meynert neurons using the conventional whole-cell patch recording configuration. Muscarine (10microM) reversibly and concentration-dependently decreased mIPSC frequency without affecting the current amplitude distribution. Muscarine action on GABAergic mIPSCs was completely blocked by 1microM methoctramine, a selective M2 receptor antagonist, but not by 1microM pirenzepine, a selective M1 receptor antagonist. NEM (10microM), a G-protein uncoupler, attenuated the inhibitory action of muscarine on GABAergic mIPSC frequency. Muscarine still could decrease GABAergic mIPSC frequency even in the Ca2+-free external solution. However, the inhibitory action of muscarine on GABAergic mIPSCs was completely occluded in the presence of forskolin. The results suggest that muscarine acts presynaptically and reduces the probability of spontaneous GABA release, and that such muscarine-induced inhibitory action seems to be mediated by G-protein-coupled M2 receptors, via the reduction of cAMP production. Accordingly, M2 receptor-mediated disinhibition of nBM neurons might play one of important roles in the regulation of cholinergic outputs from nBM neurons as well as the excitability of nBM neurons themselves.

A role of endogenous somatostatin in exocrine secretion induced by intrapancreatic cholinergic activation

A role of endogenous somatostatin in pancreatic exocrine secretion induced by intrapancreatic cholinergic activation was studied in the isolated rat pancreas perfused with modified Krebs-Henseleit solution. Intrapancreatic neurons were activated by electrical field stimulation (EFS: 15 V, 2 msec and 8 Hz). Pancreatic exocrine secretion, including volume flow and amylase output, and release of somatostatin from the pancreas were respectively determined. Somatostatin cells in the islet were stained with an immunoperoxidase method. EFS significantly increased pancreatic volume flow and amylase output, which were reduced by atropine by 59% and 78%, respectively. Intraarterial infusion of either pertussis toxin or a somatostatin antagonist resulted in a further increase in the EFS-evoked pancreatic secretion. EFS also further elevated exocrine secretion in the pancreas treated with cysteamine, which was completely restored by intraarterial infusion of somatostatin. EFS significantly increased not only the number of immunoreactive somatostatin cells in the islet but also the concentration of immunoreactive somatostatin in portal effluent. It is concluded from the above results that intrapancreatic cholinergic activation elevates pancreatic exocrine secretion as well as release of endogenous somatostatin. Endogenous somatostatin exerts an inhibitory influence on exocrine secretion induced by intrapancreatic cholinergic activation via the islet-acinar portal system in the isolated pancreas of the rat.

beta-Amyloid Neurotoxicity on Basal Forebrain Cholinergic Neuron Cultures / 대한해부학회지

beta-amyloid[Abeta] peptide consisting of 40 of 42 amino acids peptide is the principal constituent of senile plaques in Alzheimer`s disease. Recently, it has been demonstrated that this peptide and its constituent fragments are toxic to neuron. Basal forebrain cholinergic neurons are preferentially damaged early in the course of Alzheimer`s disease, and the degree of cholinergic decrement correlates well with the severity of dementia. Taking into consideration of toxic properties of Abeta and the selective vulnerability of the cholinergic system, possible effects of beta-amyloid on the cultured basal forebrain cholinergic neurons were tested. Our result showed tha Abeta1-40 induced marked neurodegenerative changes including loss of cell body and dystrophic neurites in the basal forebrain neuronal cultures at 20micrometer. Immunocytochemical study showed that Abeta1-40 causes apparent loss of choline acetyltransferase[ChAT] immunoreactivity and acetycholine esterase[AchE] positive neuritic intergrity in large basal forebrain cholinegic neurons. However, the number of ChAT immunoreactive neurons was not significantly decreased as compared to other neurons in mixed culture system. These results suggest that the basal forebrain neurons are not particularly vulnearable to Abeta and that preferential injury to basal forebrain cholinergic neurons in Alzheimer`s disease may be caused by some other medchanism.

Effect of abdominal surgery on enteric motor function and enteric nervous system in rat / 解放军医学杂志

Objective To observe the changes in enteric motor function and acetylcholine esterase(AchE)neuron and nitric oxide synthase neuron(NOS)in enteric nervous system after different abdominal operations,and to explore the mechanism of these changes.Methods Sprague Dawley rats were divided into experimental groups(laparotomy group,intestine massage group and intestinal operation group)and the control group.Rats in each group were gavaged with medicinal carbon powder,and then the transimission of carbon powder in small intestine was determined,and the spreading specimens of intestinal myenteric plexus of small intestine and large intestine were collected and stained with AchE and nicotinamide-adenine dinucleotide phosphate-D(NADPH-d)for histological study,and the density of distribution and positive stained AchE and NOS neurons were observed and compared.Results The changes in enteric motor function:the propellant rate of carbon powder was slower in enteric massage group and intestinal operation group than that in laparotomy group and control group(18.1?2.8,25.7?3.5 vs 47.4?3.6,49.8?4.5,P0.05).Compared with the control group,the number and positive expression of AchE positive neuron in intestinal myenteric plexus decreased in small intestine and large intestine in intestinal operation group and intestine massage group(small intestine 43.0?3.0,52.2?3.3 vs 65.3?3.9,P

THE STUDY OF THE DIFFERENTIATION OF NSCs MODIFIED WITH ISLET-1 GENE INTO CHOLINERGIC NEURONS / 解剖学报

Objective To explore whether Islet-1 gene of the rat could induce NSCs to differentiate into cholinergic neurons. Methods NSCs were transduced with Islet-1 recombinant retroviral expression vector.The protein expression of Islet-1 gene in NSCs was detected by immunofluorescence histochemical method.The ability of NSCs to differentiate into ChAT positive cells was observed in vivo and in vitro. Results The numbers of ChAT positive cells were significantly increased in the group of NSCs modified with Islet-1 compared with the control group in vitro.NSCs modified with Islet-1 could differentiate into ChAT positive cells when they were grafted into the corpus striatum of the adult rat brain.Conclusion Islet-1 gene could induce NSCs to differentiate into cholinergic neurons.