The acute and subchronic effects of a brain-penetrating, neurotensin-1 receptor agonist on feeding, body weight and temperature

Feifel, David; Goldenberg, Joseph R.; Melendez, Gilia; Shilling, Paul D.

doi:10.1016/j.neuropharm.2009.07.001

Cited by 47 publications

(42 citation statements)

References 23 publications

(35 reference statements)

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“…2A), suggesting the requirement of NTS1 receptors. Because PD149163 is a small-molecule NTS1 agonist that crosses the blood-brain barrier (Feifel et al, 2004(Feifel et al, , 2010Azmi et al, 2006), we tested the effects of PD149163 on neuronal excitability recorded from stellate neurons in the EC. Bath application of PD149163 (0.25 M) robustly increased the AP firing frequency (n ϭ 10, p ϭ 0.002; Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

et al. 2014

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Neurotensin (NT) is a tridecapeptide distributed in the CNS, including the entorhinal cortex (EC), a structure that is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's disease (AD). Whereas NT has been implicated in modulating cognition, the cellular and molecular mechanisms by which NT modifies cognitive processes and the potential therapeutic roles of NT in AD have not been determined. Here we examined the effects of NT on neuronal excitability and spatial learning in the EC, which expresses high density of NT receptors. Brief application of NT induced persistent increases in action potential firing frequency, which could last for at least 1 h. NT-induced facilitation of neuronal excitability was mediated by downregulation of TREK-2 K ϩ channels and required the functions of NTS1, phospholipase C, and protein kinase C. Microinjection of NT or NTS1 agonist, PD149163, into the EC increased spatial learning as assessed by the Barnes Maze Test. Activation of NTS1 receptors also induced persistent increases in action potential firing frequency and significantly improved the memory status in APP/PS1 mice, an animal model of AD. Our study identifies a cellular substrate underlying learning and memory and suggests that NTS1 agonists may exert beneficial actions in an animal model of AD.

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Section: Resultsmentioning

confidence: 99%

Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

et al. 2014

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“…In line with our previovis findings demonstrating that NTSl agonists produced potent antiallodynic effects in nerve-injured rats (21), we can thus conclude that the recruitment of both NTSl and NTS2 receptors mediates the analgesic actions of NT in chronic neuropathic pain conditions. However, since NTSl agonists were found to induce blood pressure changes and hypothermia, whereas NTS2-selective analogs did not (30,34,(72)(73)(74)(75), NTS2 analogs may therefore represent a better treatment option for painful neuropathies with a reduced side-effect profile.…”

Section: Discussionmentioning

confidence: 99%

Spinal NTS2 receptor activation reverses signs of neuropathic pain

Tétreault¹,

Beaudet²,

Perron

et al. 2013

FASEB j.

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Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and β-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.

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“…ABS-201, a new acetyl-neurotensin-(8--13) analog also induces mild hypothermia in mice [12]. NT-induced hypothermia is predominantly mediated by NTS1, since NTS1 deficient mice were completely insensitive to NT [70], and PD149163, a selective NTS1 agonist, significantly lowered core body temperature in rats [71].…”

Section: Neurotensin (Nt) Systemmentioning

confidence: 99%

Drug-Induced Hypothermia in Stroke Models: Does it Always Protect?

Zhang¹,

Wang²,

Zhao³

et al. 2013

CNSNDDT

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Ischemic stroke is a common neurological disorder lacking a cure. Recent studies show that therapeutic hypothermia is a promising neuroprotective strategy against ischemic brain injury. Several methods to induce therapeutic hypothermia have been established; however, most of them are not clinically feasible for stroke patients. Therefore, pharmacological cooling is drawing increasing attention as a neuroprotective alternative worthy of further clinical development. We begin this review with a brief introduction to the commonly used methods for inducing hypothermia; we then focus on the hypothermic effects of eight classes of hypothermia-inducing drugs: the cannabinoids, opioid receptor activators, transient receptor potential vanilloid, neurotensins, thyroxine derivatives, dopamine receptor activators, hypothermia-inducing gases, adenosine, and adenine nucleotides. Their neuroprotective effects as well as the complications associated with their use are both considered. This article provides guidance for future clinical trials and animal studies on pharmacological cooling in the setting of acute stroke. KeywordsBrain ischemia; Hypothermic; Neuroprotection; Pharmacological cooling Send correspondence to: Dr. Feng Zhang, Department of Neurology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, PA, 15213, USA, Telephone: 412-383-7604, Fax: 412-648-1239, zhanfx2@upmc.edu NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1. Hypothermia and strokes IntroductionTherapeutic hypothermia is defined as a 2-6°C reduction of core body temperature [1][2][3] and is a promising neuroprotective approach against brain injury induced by strokes. In hemorrhagic stroke, hypothermia reduces brain edema [4,5] and improves neurologic function [4][5][6][7]. In ischemic stroke, hypothermia is also protective, which has been proven in randomized clinical trials in human cardiac arrest and in animal studies of focal and global ischemia [8,9]. However, the impact of hypothermia on patients with acute ischemic stroke still needs to be explored [10]. During the past decades, studies on hypothermia and ischemic stroke have suggested that the required amplitude of protective hypothermia depends on its time of initiation relative to stroke onset, duration, and depth of hypothermia [1,9,11]. Optimal protection is typically gained when hypothermia is induced as early as possible after stroke onset, with a mild-to-moderate hypothermia of 32 to 35°C that lasts at least one to two hours [1, 2, 12-14]. Protective mechanism of hypothermia in ischemic strokeAlthough hypothermia is effective in protecting against experimental models of ischemic stroke, the precise protective mechanisms are not yet fully understood. It has been suggested that the protective mechanisms are multifold, including reductions in metabolic rate, cerebral blood flow, blood-brain barrier damage, as well as decreases in excitotoxicity, apoptosis, inflammation and free radical production [15]. On average, hypothermia red...

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The acute and subchronic effects of a brain-penetrating, neurotensin-1 receptor agonist on feeding, body weight and temperature

Cited by 47 publications

References 23 publications

Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

Spinal NTS2 receptor activation reverses signs of neuropathic pain

Drug-Induced Hypothermia in Stroke Models: Does it Always Protect?

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