Cholinergic protection via α7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation

Tyagi, Ethika; Agrawal, Rahul; Nath, Chandishwar; Shukla, Rakesh

doi:10.1016/j.neuint.2009.09.011

Cited by 86 publications

(56 citation statements)

References 41 publications

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“…These results illustrate the modulatory effect of both AChE inhibitors on neuroinflammation as shown before in clinical and experimental studies with donepezil [13,45]. Physostigmine and donepezil per se did not affect IL-1β and TNF-α levels, indicating that both AChE inhibitors only act to normalize the induced proinflammatory cytokines (fig.…”

Section: Discussionsupporting

confidence: 84%

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Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

et al. 2013

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The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation employing acetylcholine as the key endogenous mediator. In this study, we investigated the effects of the cholinergic agonists, physostigmine and donepezil, on neurodegeneration, inflammation and oxidative stress during oxygen toxicity in the developing rat brain. The aim of this study was to investigate the level of neurodegeneration, expression of proinflammatory cytokines, glutathione and lipid peroxidation after hyperoxia and treatment with the acetylcholinesterase (AChE) inhibitors, physostigmine and donepezil in the brain of neonatal rats. Six-day-old Wistar rats were exposed to 80% oxygen for 12-24 h and received 100 μg/kg physostigmine or 200 μg/kg donepezil intraperitoneally. Sex-matched littermates kept in room air and injected with normal saline, physostigmine or donepezil served as controls. Treatment with both inhibitors significantly reduced hyperoxia-triggered activity of AChE, neural cell death and the upregulation of the proinflammatory cytokines IL-1β and TNF-α in the immature rat brain on the mRNA and protein level. In parallel, hyperoxia-induced oxidative stress was reduced by concomitant physostigmine and donepezil administration, as shown by an increased reduced/oxidized glutathione ratio and attenuated malondialdehyde levels, as a sign of lipid peroxidation. Our results suggest that a single treatment with AChE inhibitors at the beginning of hyperoxia attenuated the detrimental effects of oxygen toxicity in the developing brain and may pave the way for AChE inhibitors, which are currently used for the treatment of Alzheimer's disease, as potential candidates for adjunctive neuroprotective therapies to the immature brain.

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Section: Discussionsupporting

confidence: 84%

“…Antisense suppression of AChE production reduces the level of proinflammatory cytokines in spinal cord neurons of primates [12]. AChE inhibitors increase the availability of ACh in central cholinergic synapses and are the most promising currently available drugs for the treatment of Alzheimer's disease (AD) [13]. …”

Section: Introductionmentioning

confidence: 99%

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

et al. 2013

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“…Similar observations were made in rats pre-treated with MLA and the anticholinesterasic agent donepezil and then, submitted to lipopolysaccharide (LPS) intracerebroventricular injection. MLA, but not dihydro--erytroidine (an 4 2 receptor antagonist) or scopolamine (a muscarinic receptor antagonist) reduced the antiinflammatory effect of donepezil [46], showing, once again, the participation of 7 nAChR in the efferent way of the inflammatory reflex, which also involves the efferent vagus nerve and, obviously, the neurotransmitter acetylcholine [47]. This possible antiinflammatory reaction is being further investigated by our research team.…”

Section: Increases In 7 Density Can Also Be Re-lated To a Central Antmentioning

confidence: 88%

Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain

Viel

Caetano²,

Albuquerque³

et al. 2012

CAR

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2012Chronic infusion of amyloid-peptide and sustained attention altered 7 nicotinic receptor density in the rat brain Current Alzheimer Research, Sharjah, v. 9, n. 10, supl., Part 2, pp. 1210-1220, dec, 2012 Abstract: It is already known that progressive degeneration of cholinergic neurons in brain areas such as the hippocampus and the cortex leads to memory deficits, as observed in Alzheimer's disease. This work verified the effects of the infusion of amyloid-(A ) peptide associated to an attentional rehearsal on the density of 7 nicotinic cholinergic receptor (nAChR) in the brain of male Wistar rats. Animals received intracerebroventricular infusion of A or vehicle (control -C) and their attention was stimulated weekly (Stimulated A group: S-A and Stimulated Control group: SC) or not (NonStimulated A group: N-SA and Non-Stimulated Control group: N-SC), using an active avoidance apparatus. Conditioned avoidance responses (CAR) were registered. Chronic infusion of A caused a 37% reduction in CAR for N-SA . In S-A , this reduction was not observed. At the end, brains were extracted and autoradiography for 7 nAChR was conducted using [125 I]--bungarotoxin. There was an increase in 7 density in hippocampus, cortex and amygdala of SA animals, together with the memory preservation. In recent findings from our lab using mice infused with A and the 7 antagonist methyllycaconitine, and stimulated weekly in the same apparatus, it was observed that memory maintenance was abolished. So, the increase in 7 density in brain areas related to memory might be related to a participation of this receptor in the long-lasting change in synaptic plasticity, which is important to improve and maintain memory consolidation.

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“…Other signals involved in the anti-inflammatory mechanisms of α7nAChR were also present effectively. Taking PI3K-Akt pathway for example, activity of PI3K-Akt was significantly enhanced after treatment with donepezil that could activate α7nAChR, followed by alleviatived neuro-inflammation 88. In addition, activation of α7nAChR distinctly diminished TLR4 expression via increasing PI3K/Akt activation, thereby leading to reduction of inflammatory cytokines and improvement of sepsis survival 89.…”

Section: Molecular Mechanisms Of α7nachr Actionmentioning

confidence: 99%

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Ren

Tong

et al. 2017

Int. J. Biol. Sci.

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Critical illnesses and injuries are recognized as major threats to human health, and they are usually accompanied by uncontrolled inflammation and dysfunction of immune response. The alpha 7 nicotinic acetylcholine receptor (α7nAchR), which is a primary receptor of cholinergic anti-inflammatory pathway (CAP), exhibits great benefits for critical ill conditions. It is composed of 5 identical α7 subunits that form a central pore with high permeability for calcium. This putative structure is closely associated with its functional states. Activated α7nAChR exhibits extensive anti-inflammatory and immune modulatory reactions, including lowered pro-inflammatory cytokines levels, decreased expressions of chemokines as well as adhesion molecules, and altered differentiation and activation of immune cells, which are important in maintaining immune homeostasis. Well understanding of the effects and mechanisms of α7nAChR will be of great value in exploring effective targets for treating critical diseases.

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Cholinergic protection via α7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation

Cited by 86 publications

References 41 publications

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

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Cholinergic protection via α7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation

Cited by 86 publications

References 41 publications

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

Chronic Infusion of Amyloid-&beta; Peptide and Sustained Attention Altered &alpha;7 Nicotinic Receptor Density in the Rat Brain

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

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Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain