1400W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in the rat kainate model of temporal lobe epilepsy

Puttachary, Sreekanth; Sharma, Shaunik; Verma, Saurabh; Yang, Yang; Putra, Marson; Thippeswamy, Achala; Luo, Diou; Thippeswamy, Thimmasettappa

doi:10.1016/j.nbd.2016.05.013

Cited by 59 publications

(147 citation statements)

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“…Such inflammatory response promotes reactive astrogliosis, which persisted in the CA3 region even 30 days after KA injection when measured by immunoreactivity to the astrocyte marker, viz glial fibrillary acidic protein [46]. Neuroinflammation by the M1 microglia is sometimes accompanied by an upregulation of inducible nitric oxide synthase ([47] and references cited therein). In one kainate model [48], the production of nitric oxide in the hippocampus peaked at 8 h after status epilepticus and the elevated levels persisted for 6 weeks.…”

Section: Discussionmentioning

confidence: 99%

Faster flux of neurotransmitter glutamate during seizure — Evidence from 13C-enrichment of extracellular glutamate in kainate rat model

Kanamori

2017

PLoS ONE

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The objective is to examine how the flux of neurotransmitter glutamate from neurons to the extracellular fluid, as measured by the rate of 13C enrichment of extracellular glutamate (GLUECF), changes in response to seizures in the kainate-induced rat model of temporal-lobe epilepsy. Following unilateral intrahippocampal injection of kainate, GLUECF was collected by microdialysis from the CA1/CA3 region of awake rats, in combination with EEG recording of chronic-phase recurrent seizures and intravenous infusion of [2,5-13C]glucose. The 13C enrichment of GLUECF C5 at ~ 10 picomol level was measured by gas-chromatography mass-spectrometry. The rate of 13C enrichment, expressed as the increase of the fractional enrichment/min, was 0.0029 ± 0.0001/min in frequently seizing rats (n = 4); this was significantly higher (p < 0.01) than in the control (0.00167 ± 0.0001/min; n = 6) or in rats with infrequent seizures (0.00172 ± 0.0001/min; n = 6). This result strongly suggests that the flux of the excitatory neurotransmitter from neurons to the extracellular fluid is significantly increased by frequent seizures. The extracellular [12C + 13C]glutamate concentration increased progressively in frequently seizing rats. Taken together, these results strongly suggest that the observed seizure-induced high flux of glutamate overstimulated glutamate receptors, which triggered a chain reaction of excitation in the CA3 recurrent glutamatergic networks. The rate of 13C enrichment of extracellular glutamine (GLNECF) at C5 was 0.00299 ± 0.00027/min in frequently seizing rats, which was higher (p < 0.05) than in controls (0.00227 ± 0.00008/min). For the first time in vivo, this study examined the effects of epileptic seizures on fluxes of the neurotransmitter glutamate and its precursor glutamine in the extracellular fluid of the hippocampus. The advantages, limitations and the potential for improvement of this approach for pre-clinical and clinical studies of temporal-lobe epilepsy are discussed.

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Section: Discussionmentioning

confidence: 99%

Faster flux of neurotransmitter glutamate during seizure — Evidence from 13C-enrichment of extracellular glutamate in kainate rat model

Kanamori

2017

PLoS ONE

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“…Inducible NOS is mainly present in inflammatory cells, and inhibition of this may reduce inflammation and neuroprotect following status epilepticus [71]. Nitric oxide, which usually plays an important physiological role, when overproduced can combine with reactive oxygen species (see below) to produce peroyxnitrite, which at high concentrations is neurotoxic resulting in DNA injury, lipid peroxidation, impairment of cellular signaling, and mitochondrial dysfunction [72,73].…”

Section: Enzymes Activated By Intracellular Calcium Accumulationmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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“…Therefore, targeting them to arrest the advancement of the disease is rather resoundingly relevant. Of particular interest is iNOS, an enzyme responsible for production of copious NO levels manifested in inflammation [80] (Figure 2). However, targeting such an enzyme that exhibits such a critical role in body physiology requires a high level of specificity to circumvent any possible collateral damage that might come along with the nonspecific inhibition such as targeting enzyme sites: arginine, heme, and tetrahydrobiopterin (BH4) sites [78].…”

Section: Therapeutic Strategies Targeting No Signaling Pathwaysmentioning

confidence: 99%

“…Compounds that target and inhibit reactivation of glial cells have been investigated [80]. Thippeswamy and his colleagues investigated compound 1400 W, an inhibitor of NOS.…”

Section: Therapeutic Strategies Targeting No Signaling Pathwaysmentioning

confidence: 99%

“…It was also found to act on glutamate transporter-1 (GLT-1) levels but insignificantly. It was concluded that the compound was much more effective against gliosis but with a higher level of effectiveness could be realized when supplemented with an anti-inflammatory agent [80]. Although targeting the glial cells presents a safer strategy, manipulating the enzymes would be a much more effective course of action.…”

Section: Therapeutic Strategies Targeting No Signaling Pathwaysmentioning

confidence: 99%

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Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease

Nicholas

Yeo

Kim

et al. 2016

Oxidative Medicine and Cellular Longevity

102

116

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Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO.

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1400W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in the rat kainate model of temporal lobe epilepsy

Cited by 59 publications

References 139 publications

Faster flux of neurotransmitter glutamate during seizure — Evidence from 13C-enrichment of extracellular glutamate in kainate rat model

Faster flux of neurotransmitter glutamate during seizure — Evidence from 13C-enrichment of extracellular glutamate in kainate rat model

Pathophysiology of status epilepticus

Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease

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