Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats

Günther, Mattias; Davidsson, Johan; Plantman, Stefan; Norgren, Svante; Mathiesen, Tiit; Risling, Mårten

doi:10.1016/j.jocn.2015.03.025

Cited by 28 publications

(32 citation statements)

References 41 publications

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“…The blood brain barrier (BBB) permeability of NACA has been demonstrated using cell lines and rodent models of PD and AD (Sunitha et al ., ). NACA has recently been shown to prevent neuronal degeneration following focal penetrating traumatic brain injury in rats (Günther et al ., ) and may ultimately prove to be a more effective therapy than NAC for neurodegenerative disorders.…”

Section: Thiol‐based Redox Therapies In Neurodegenerative Diseasementioning

confidence: 99%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

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Section: Thiol‐based Redox Therapies In Neurodegenerative Diseasementioning

confidence: 99%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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“…Unsatisfactory control or medical intractability, is defined as the failure of two pharmacological agents to control seizures, and is predicted by the presence of neurologic structural anomalies in the temporal cortex, often found in PTE [74]. Further research is being conducted to investigate the protective properties of supplements such as nacetyl cysteine and progesterone to treat PTE, but the results are so far inconclusive [79,80]. In patients failing medical management, surgical resection may be an option if a seizure focus can be identified on imaging and/or electrophysiological studies [4].…”

Section: Treatment Options For Drug-resistant Ptementioning

confidence: 99%

Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure

Lucke‐Wold

Nguyen

Turner

et al. 2015

Seizure

119

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Post-traumatic epilepsy continues to be a major concern for those experiencing traumatic brain injury. Post-traumatic epilepsy accounts for 10-20% of epilepsy cases in the general population. While seizure prophylaxis can prevent early onset seizures, no available treatments effectively prevent late-onset seizure. Little is known about the progression of neural injury over time and how this injury progression contributes to late onset seizure development. In this comprehensive review, we discuss the epidemiology and risk factors for post-traumatic epilepsy and the current pharmacologic agents used for treatment. We highlight limitations with the current approach and offer suggestions for remedying the knowledge gap. Critical to this pursuit is the design of pre-clinical models to investigate important mechanistic factors responsible for post-traumatic epilepsy development. We discuss what the current models have provided in terms of understanding acute injury and what is needed to advance understanding regarding late onset seizure. New model designs will be used to investigate novel pathways linking acute injury to chronic changes within the brain. Important components of this transition are likely mediated by toll-like receptors, neuroinflammation, and tauopathy. In the final section, we highlight current experimental therapies that may prove promising in preventing and treating post-traumatic epilepsy. By increasing understanding about post-traumatic epilepsy and injury expansion over time, it will be possible to design better treatments with specific molecular targets to prevent late-onset seizure occurrence following traumatic brain injury.

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“…NACA may even have neuroprotective properties after focal penetrating brain injuries [14]. Markers of inflammation, including the cytokines IL-1β, IL-6 and TNFα, are correlated with the severity and clinical outcome after perinatal asphyxia [15].…”

Section: Introductionmentioning

confidence: 99%

N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

et al. 2016

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Background: Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs. Objectives: To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-κB in the prefrontal cortex of neonatal pigs. Methods: Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the base excess was -20 mmol/l or the mean arterial blood pressure fell to <20 mm Hg (asphyxia with NACA or saline). The pigs were observed for 9.5 h after hypoxia. Samples of prefrontal cortex and plasma were analyzed. Results: Cortex: there was no significant difference in mRNA expression between the intervention groups regarding IL-1β, IL6, TNFα, MMP2, MMP9 or IL18. Pigs exposed to hypoxia-reoxygenation and treatment with NACA (NACA-pigs) had a significantly lower protein concentration of IL-1β than pigs treated with saline (placebo controls), i.e. 8.8 ± 3.9 versus 16.8 ± 10.5 pg/mg protein (p = 0.02). The activation of the transcription factor NF-κB (measured as the fold-change of phosphorylated p65^{Ser 536}), was reduced in the NACA-pigs when compared to the placebo controls (5.2 ± 4.3 vs. 16.0 ± 13.5; p = 0.02). No difference between the intervention groups regarding brain histopathology or in the levels of 8-oxoguanine measured in the prefrontal cortex were observed. Plasma: the NACA-pigs had a stronger reduction of TNFα in the first 30 min following asphyxia compared with the placebo controls, i.e. 36 (30-44) versus 24 (14-32)% (p = 0.01). Conclusion: The reduced levels of the pivotal inflammatory markers IL-1β and TNFα and the transcription factor NF-κB may indicate that NACA has possible neuroprotective effects after perinatal asphyxia.

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Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats

Cited by 28 publications

References 41 publications

Redox‐based therapeutics in neurodegenerative disease

Redox‐based therapeutics in neurodegenerative disease

Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure

N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

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