NK1 tachykinin receptor treatment is superior to capsaicin pre-treatment in improving functional outcome following acute ischemic stroke

doi:10.1016/j.npep.2014.07.002

Neuropeptides

Volume 48, Issue 5, October 2014, Pages 267-272

https://doi.org/10.1016/j.npep.2014.07.002 Get rights and content

Highlights

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NK1 receptor antagonist improves outcome.
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NK1 receptor antagonist superior to capsaicin pre-treatment.
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Blocking the action of neuropeptides post-stroke improves functional outcome.

Abstract

Previous results from our laboratory have shown that blockade of the substance P (SP) pathway with an NK1 tachykinin receptor antagonist significantly reduces blood brain barrier breakdown, cerebral edema and functional deficits following ischemic stroke. However, it is unclear whether removal of all neuropeptides is more efficacious than blocking SP alone. As such, the aim of the present study was to determine the effect of neuropeptide depletion with capsaicin pre-treatment on functional outcome following acute ischemic stroke in rats. Animals received 125 mg/kg of capsaicin or equal volume of saline vehicle, administered subcutaneously over a 3-day period. At 14 days following treatment animals were subject to 2 h of middle cerebral artery occlusion followed by reperfusion. A subset of animals was treated with an NK1 tachykinin receptor antagonist (NAT) or vehicle at 4 h after the onset of stroke only. The functional outcome of animals was assessed for a 7-day period following stroke using a rotarod device, the bilateral asymmetry test, modified neurological severity score, open field and angleboard. Although capsaicin pre-treatment improved outcome, treatment with an NK1 tachykinin receptor antagonist was superior in improving post-stroke functional outcome. This data suggests that some neuropeptides may play a beneficial role following stroke, whilst others such as SP are deleterious.

Introduction

Our laboratory has recently demonstrated that the neuropeptide substance P (SP) is increased following ischemic stroke (Turner and Vink, 2007, Turner et al., 2006, Turner et al., 2011) and is associated with the development of neurogenic inflammation and subsequent blood–brain barrier (BBB) dysfunction, cerebral edema and functional deficits (Turner and Vink, 2007, Turner et al., 2006, Turner et al., 2011, Turner and Vink, 2012). Blocking the action of SP with an NK1 tachykinin receptor antagonist is highly efficacious in improving post-stroke outcome through a reduction in BBB permeability, cerebral edema and functional deficits (Turner et al., 2011, Turner and Vink, 2012). However, these studies specifically focused on the SP pathway only and it is therefore unclear what role other neuropeptides may play following stroke.

Capsaicin, an agent isolated from chilli peppers, is able to stimulate the release of sensory neuropeptides, including SP and calcitonin gene-related peptide (CGRP), to the point of depletion (Kashiba et al., 1997, Wimalawansa, 1996). In neonatal animals, capsaicin treatment produces permanent sensory neuropeptide depletion, whereas in adults it produces transient sensory neuropeptide depletion, reported to last for at least 3 weeks (Kashiba et al., 1997). Although the effects on levels of individual neuropeptides is highly dependent on the capsaicin dosing regime. Nevertheless, capsaicin treatment is an extremely useful experimental tool to study the functions of various neuropeptides. Indeed, our laboratory has shown that pre-treatment with capsaicin markedly improves outcome following diffuse traumatic brain injury (TBI) by reducing BBB dysfunction, cerebral edema and functional deficits (Nimmo et al., 2004, Vink et al., 2003). The fact that the protection conferred by capsaicin was almost identical to that conferred by NK1 tachykinin receptor antagonists confirmed a dominant role for SP following injury to the brain. As such, we sought to determine whether the depletion of all neuropeptides by capsaicin similarly conveys any protection from the development of functional deficits following stroke, and whether it was superior to blockade of SP alone.

Section snippets

Materials and methods

All experimental protocols were approved by the Animal Ethics Committees of the University of Adelaide and were conducted according to guidelines established for the use of animals in experimental research as outlined by the Australian National Health and Medical Research Council (8th Edition 2013).

Results

There was no significant difference (p > 0.05; results not shown) observed between the vehicle pre-treatment and post-treatment groups, demonstrating that injured animals perform similarly, irrespective of the time or route of vehicle administration. As such, the data for these groups was combined and they are represented as the “vehicle” group on all of the functional outcome measures. A summary of the statistical comparisons between all groups for the functional outcome tests is shown in Table 1

Discussion

We demonstrate that depletion of neuropeptides prior to cerebral ischaemia results in attenuation of functional deficits. Indeed, a role for neuropeptides and neurogenic inflammation in BBB dysfunction, cerebral edema and functional deficits following ischemic stroke (Turner and Vink, 2007, Turner et al., 2006, Turner et al., 2011) and TBI (Donkin et al., 2009, Donkin et al., 2007, Nimmo et al., 2004, Vink et al., 2004) has recently been demonstrated.

In the present study, pre-treatment with

Acknowledgement

This work was supported, in part, by the National Health and Medical Research Council (NHMRC) of Australia.

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Correcting a widespread error: Neuroprotectant N-acetyl-L-tryptophan does not bind to the neurokinin-1 receptor
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Citation Excerpt :
In the literature there are several reports on the neuroprotective action of N-acetyl-L-tryptophan (NAT, 1, Fig. 1). A few groups studied the effects of this compound in the context of traumatic brain injury (Ameliorate et al., 2017; Carthew et al., 2012; Corrigan et al., 2021, 2012; Donkin et al., 2011, 2009; Gabrielian et al., 2013; Vink et al., 2004), ischaemic stroke (Turner et al., 2011; Turner and Vink, 2014, 2012), subarachnoid haemorrhage (Barry et al., 2011), spinal cord injury (Leonard et al., 2014; Leonard and Vink, 2013), Parkinson's disease (Thornton et al., 2010; Thornton and Vink, 2012a), Alzheimer's disease (Fernandes et al., 2018) or amyotrophic lateral sclerosis (Li et al., 2015; Sirianni et al., 2015). In most of these papers, NAT treatment yielded positive effects and provided neuroprotection (Tables 1–3 in the Discussion section).
N-acetyl-L-tryptophan (NAT) has been often shown to have neuroprotective action and other biological activities. In many of papers devoted to this compound, NAT is referenced to as an ‘NK1 receptor (NK1R) antagonist’ or a ‘substance P (SP) antagonist’. Some of the studies treated NAT as a tool compound to interrogate NK1R function in a particular condition. Surprisingly however, no biochemical data on NAT/NK1R interaction have been available. On testing NAT in radioligand receptor binding assay, we found that this compound displays no significant binding to either human or rat NK1R up to millimolar concentrations. In light of this, the repeated claim of NAT being NK1R antagonist is an error. The use of NAT as a tool compound in NK1R-related studies should be discontinued. Some of the conclusions regarding the involvement of SP/NK1R axis in acute CNS injury or neurodegenerative diseases may then require careful rethinking. On the other hand, given interesting neuroprotective properties of NAT, the issue whether it acts by specific interactions with some molecular target or by unspecific physicochemical mechanisms needs be investigated.
Serum substance P levels and early mortality of spontaneous intracerebral haemorrhage patients
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However, similar findings were found in the studies from our team with traumatic brain injury34 or brain infarction.35 The administration of neurokinin 1 receptor (NK1R) antagonists, therefore antagonists of receptor of substance P, have reduced brain vascular permeability, cerebral edema, intracranial pressure, and functional deficits in animal models of traumatic brain injury27–33 or cerebral ischemia.36–40 Thus, it is possible that the NK1R antagonist administration in ICH patients could reduce the activity of substance P and therefore the secondary brain injury (by minimizing neuroinflammation, vascular permeability and cerebral edema), functional impairment, and risk of death.
Substance P, a neuropeptide of the tachykinin family, is involved in the neuroinflammation of different diseases of the central nervous system. To our knowledge, there is no published data on the level of circulating substance P levels in the prognosis of patients with spontaneous intracerebral hemorrhage (ICH). Therefore, the objectives of this observational and prospective study were to determine whether serum substance P levels in ICH patients were associated with early mortality and whether could be used in the mortality prognostic.
We included patients with severe primary supratentorial ICH (defined as Glasgow Coma Scale < 9) from 6 Intensive Care Units of Spanish hospitals. We determined serum substance P levels at the time of severe ICH diagnosis, at fourth and at eighth day. Thirty-day mortality was considered the end-point study.
Non-surviving (n=53) compared to surviving ICH patients (n=64) showed higher serum substance P levels at day 1 (p<0.001), day 4 (p<0.001) and day 8 (p<0.001). The area under the curve for 30-day mortality prediction by serum substance P levels was of 79% (95% CI = 70–86%; p<0.001). Kaplan–Meier analysis showed a higher 30-day mortality in patients with serum substance P levels>503 pg/mL (Hazard ratio=14.7; 95% CI=6.88–31.55; p<0.001). Multiple logistic regression analysis showed an association between serum substance P levels and 30-day mortality (Odds Ratio=1.006; 95% CI=1.002–1.010; p=0.004) controlling for ICH score, midline shift, glycemia, early evacuation of ICH.
Thus, the novel aspects our study include that serum substance P levels in severe primary ICH patients were higher in non-surviving than in surviving patients, that serum substance P levels were associated with early mortality controlling for other variables, and that serum substance P levels could be used as biomarkers of prognosis.
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It is also involved in different diseases such as inflammatory bowel disease, asthma and central and peripheral nervous systems diseases [5–7]. Substance P has been found to participate in the neuroinflammation of animal models of cerebral ischemia [8–15]. It has also been scarcely studied in ischemic stroke patients [16–18].
Previously our team found higher serum substance P concentrations at day 1 of a malignant middle cerebral artery infarction (MMCAI) in non-surviving than in surviving patients. Thus, the objective of this study was to determine whether serum substance P levels during the first week of MMCAI could predict mortality.
We included patients with MMCAI defined as computed tomography findings of acute infarction in at least of 50% of the territory and Glasgow Coma Scale ≤8. We determined serum concentrations of substance P on days 1, 4 and 8 of MMCAI. Thirty-day mortality was the study end-point.
Serum substance P concentrations at days 1 (p < .001), 4 (p < .001), and 8 (p = .001) of MMCAI in non-surviving (n = 34) were higher than in surviving patients (n = 34). Receiver operating characteristic analyses showed that serum substance P concentrations at days 1, 4, and 8 of MMCAI had an area under curve (95% confidence intervals) to predict 30-day mortality of 0.77 (0.66–0.87; p < .001), 0.82 (0.69–0.91; p < .001) and 0.85 (0.72–0.94; p < .001) respectively.
The two new findings of our study are that non-surviving MMCAI patients showed higher serum substance P levels at day 1, 4 and 8 than surviving, and that those levels could predict 30-day mortality.
Capsaicin produces antidepressant-like effects in the forced swimming test and enhances the response of a sub-effective dose of amitriptyline in rats
2018, Physiology and Behavior
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Thus, the potentiation found between Ami and Cap to reduce the immobility of rats in the FST opens the possibility of minimizing the adverse effects of tricyclic antidepressants by administering lower doses in combination with low doses of TRPV1 agonists. It has been reported that TRPV1 activation does not increase general locomotion in the OFT [5,7,42,46], which is in line with our results. The fact that Cap alone and combined with Ami did not augment the ambulation in the OFT, reinforces the idea that the anti-immobility effect of Cap in the FST is not a false positive but a real antidepressant property of the TRPV1 agonist.
Transient receptor potential vanilloid 1 (TRPV1) channels have been implicated in depression and anxiety. The aim of this study was to evaluate the antidepressant-like properties of the TRPV1 agonist capsaicin using the forced swimming test (FST) in rats. Capsaicin (0.001–0.25 mg/kg, i.p.) produced a reduction of immobility in the FST. A maximally effective dose of the tricyclic antidepressant amitriptyline (12 mg/kg) reduced immobility as well. Notably, doses of capsaicin (1 pg/kg, 1 ng/kg, and 0.001 mg/kg) that were ineffective when applied alone produced a significant decrease in immobility when combined with a subthreshold dose of amitriptyline (5 mg/kg). Rats treated with capsaicin (0.01 mg/kg) + amitriptyline (5 mg/kg) displayed less immobility than those treated with a maximally effective dose of amitriptyline. The non-pungent TRPV1 channel agonist palvanil (0.05–0.1 mg/kg, i.p.) also decreased immobility in the FST. Capsaicin (0.05 mg/kg) did not affect general locomotion in the open field test, nor performance in the elevated plus maze, or skeletal muscle contraction strength measured in vitro after the FST (at 0.25 mg/kg). Altogether, our results imply that low doses of capsaicin produce antidepressant-like effects, and enhance the effect of a subthreshold dose of amitriptyline in the FST.
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NK1 tachykinin receptor treatment is superior to capsaicin pre-treatment in improving functional outcome following acute ischemic stroke

Highlights

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgement

Biochem. Biophys. Res. Comm.

Brain Behav. Immun.

Immunopharmacology

Neuropeptides

Prog. Brain Res.

Physiol. Behav.

Gen. Pharmacol.

Eur. J. Pharmacol.

Regul. Pept.

J. Neurosci. Methods

Neuropeptides

Peptides

Neuroscience

Brain Res.

Eur. J. Pharmacol.

Expression of functional NK1 receptors in human alveolar macrophages: superoxide anion production, cytokine release and involvement of NF-kappaB pathway

Br. J. Pharmacol.

Spatiotemporal relationship of apoptotic cell death to lymphomonocytic infiltration in photochemically induced focal ischemia of the rat cerebral cortex

Acta Neuropathol.

Use of NK(1) knockout mice to analyze substance P-induced edema formation

Am. J. Physiol.

A ligand–receptor pair that triggers a non-apoptotic form of programmed cell death

Cell Death Diff.

Stimulation of sensory nerves and CGRP attenuate pancreatic damage in ischemia/reperfusion induced pancreatitis

Med. Sci. Monit.

Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury

J. Cereb. Blood Flow Metab.

The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B

J. Immunol.

Interleukin-1beta upregulates functional expression of neurokinin-1 receptor (NK-1R) via NF-kappaB in astrocytes

Glia