Oxidative stress and energy depletion are believed to participate in hippocampal neuronal damage after forebrain ischemia. This study has been initiated to investigate the potential neuroprotective effects of probucol, a lipid-lowering drug with strong antioxidant properties, against transient forebrain ischemia-induced neuronal damage and biochemical abnormalities in rat hippocampal CA1 region. Adult male Wistar albino rats were subjected to forebrain ischemia and injected with probucol for the next 7 successive days, and compared to controls. Forebrain ischemia resulted in a significant decrease in the number of intact neurons (77&#x25;), glutathione (GSH), and adenosine triphosphate (ATP), and a significant increase in thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite, (NOx) production in hippocampal tissues. The administration of probucol attenuated forebrain ischemia-induced neuronal damage, manifested as a complete reversal of the decrease in the number of intact neurons, ATP and GSH and the increase in TBARS and NOx in hippocampal tissues. This study demonstrates that probucol treatment abates forebrain ischemia-induced hippocampal neuronal loss, energy depletion, and oxidative stress in hippocampal CA1 region. Thus, probucol could be a promising neuroprotective agent in the treatment of forebrain ischemia.

Abdulhakeem A. Al-Majed

Probucol Attenuates Oxidative Stress, Energy Starvation, and Nitric Acid Production Following Transient Forebrain Ischemia in the Rat Hippocampus

Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer and has adverse side effects such as nephrotoxicity and hepatotoxicity. The present study was designed to determine the effects of royal jelly (RJ) against oxidative stress caused by CDDP injury of the kidneys and liver, by measuring tissue biochemical and antioxidant parameters and investigating apoptosis immunohistochemically. Twenty-four Sprague Dawley rats were divided into four groups, group C: control group received 0.9% saline; group CDDP: injected i.p. with cisplatin (CDDP, 7 mg kg-1 body weight i.p., single dose); group RJ: treated for 15 consecutive days by gavage with RJ (300 mg/kg/day); group RJ + CDDP: treated by gavage with RJ 15 days following a single injection of CDDP. Malondialdehyde (MDA) and glutathione (GSH) levels, glutathione S-transferase (GST), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities were determined in liver and kidney homogenates, and the liver and kidney were also histologically examined. RJ elicited a significant protective effect towards liver and kidney by decreasing the level of lipid peroxidation (MDA), elevating the level of GSH, and increasing the activities of GST, GSH-Px, and SOD. In the immunohistochemical examinations were observed significantly enhanced apoptotic cell numbers and degenerative changes by cisplatin, but these histological changes were lower in the liver and kidney tissues of RJ + CDDP group. Besides, treatment with RJ lead to an increase in antiapoptotic activity hepatocytes and tubular epithelium. In conclusion, RJ may be used in combination with cisplatin in chemotherapy to improve cisplatin-induced oxidative stress parameters and apoptotic activity.

Ali Karadeniz

Nejdet Simsek

Emre Karakus

Serap Yildirim

Adem Kara

Ismail Can

Fikrullah Kisa

Habib Emre

Mehmet Turkeli

Royal Jelly Modulates Oxidative Stress and Apoptosis in Liver and Kidneys of Rats Treated with Cisplatin

Bitter orange (Citrus aurantium) extract and its primary protoalkaloid p-synephrine are used widely in weight loss/weight management and sports performance products. Because of structural similarities, the pharmacological effects of p-synephrine are widely assumed to be similar to those of ephedrine, m-synephrine (phenylephrine), and endogenous amine neurotransmitters as norepinephrine and epinephrine. However, small structural changes result in the receptor binding characteristics of these amines that are markedly different, providing a plausible explanation for the paucity of adverse effects associated with the wide-spread consumption of p-synephrine in the form of dietary supplements as well as in various Citrus foods and juices. This paper summarizes the adrenoreceptor binding characteristics of p-synephrine relative to m-synephrine, norepinephrine, and other amines as related to the observed pharmacological effects.

Sidney J. Stohs

Harry G. Preuss

Mohd Shara

A Review of the Receptor-Binding Properties of p-Synephrine as Related to Its Pharmacological Effects

It is generally believed that diseases caused by oxidative stress should be treated with antioxidants. However, clinical trials with such antioxidants as ascorbic acid and vitamin E, failed to produce the expected beneficial results. On the other hand, important biomolecules can be modified by the introduction of oxygen atoms by means of non-oxidative hydroxyl radicals.  In addition, hydroxyl radicals can reduce disulfide bonds in proteins, specifically fibrinogen, resulting in their unfolding and scrambled refolding into abnormal spatial configurations. Consequences of this reaction are observed in many diseases such as atherosclerosis, cancer and neurological disorders, and can be prevented by the action of non-reducing substances.  Moreover, many therapeutic substances, traditionally classified as antioxidants, accept electrons and thus are effective oxidants.  It is described in this paper that hydroxyl radicals can be generated by ferric ions without any oxidizing agent. In view of the well-known damaging effect of poorly chelated iron in the human body, numerous natural products containing iron binding agents can be essential in the maintenance of human health.  However, beneficial effects of the great number of phytochemicals that are endowed with hydroxyl radical scavenging and/or iron chelating activities should not be considered as a proof for oxidative stress.

Boguslaw Lipinski

Hydroxyl Radical and Its Scavengers in Health and Disease

Prophylactic pharmacological activation of astrocytic gene expression driven by the transcription factor Nrf2 boosts antioxidant defences and protects against neuronal loss in ischemia and other disease models. However, the role of Nrf2 in mediating endogenous neuroprotective responses is less clear. We recently showed that Nrf2 is activated by mild oxidative stress in both rodent and human astrocytes. Moreover, brief exposure to ischemic conditions was found to activate Nrf2 both in vivo and in vitro, and this was found to contribute to neuroprotective ischemic preconditioning. Here we show that transient ischemic conditions in vitro and in vivo cause an increase in the expression of Nrf2 target genes associated with the glutathione pathway, including those involved in glutathione biosynthesis and cystine uptake. Taken together, these studies indicate that astrocytic Nrf2 may represent an important mediator of endogenous neuroprotective preconditioning pathways.

Karen F. S. Bell

Jill H. Fowler

Bashayer Al-Mubarak

Karen Horsburgh

Giles E. Hardingham

Activation of Nrf2-Regulated Glutathione Pathway Genes by Ischemic Preconditioning

Ethanol-induced neuro-developmental abnormalities are associated with impaired insulin and IGF signaling, and increased oxidative stress in CNS neurons. We examined the roles of ethanol and its principal toxic metabolite, acetaldehyde, as mediators of impaired insulin/IGF signaling and oxidative injury in immature cerebellar neurons. Cultures were exposed to 3.5 mM acetaldehyde or 50 mM ethanol ± 4-methylpyrazole (4-MP), an inhibitor of ethanol metabolism, and viability, mitochondrial function, oxidative stress, DNA damage, and insulin responsiveness were measured 48 hours later. Acetaldehyde or ethanol increased neuronal death and levels of 8-OHdG and 4-HNE, and reduced mitochondrial function. Ethanol inhibited insulin responsiveness, whereas acetaldehyde did not. 4-MP abated ethanol-induced oxidative stress and mitochondrial dysfunction, but failed to restore insulin responsiveness. Furthermore, alcohol and aldehyde metabolizing enzyme genes were inhibited by prenatal ethanol exposure; this effect was mediated by acetaldehyde and not ethanol + 4MP. These findings suggest that brain insulin resistance in prenatal alcohol exposure is caused by direct effects of ethanol, whereas oxidative stress induced neuronal injury is likely mediated by ethanol and its toxic metabolites. Moreover, the adverse effects of prenatal ethanol exposure on brain development may be exacerbated by down-regulation of genes needed for metabolism and detoxification of alcohol in the brain.

Ming Tong

Lisa Longato

Quynh-GiaoLy Nguyen

William C. Chen

Amy Spaisman

Suzanne M. de la Monte

Acetaldehyde-Mediated Neurotoxicity: Relevance to Fetal Alcohol Spectrum Disorders

Sphingosine kinase (SphK) exhibits two isoforms, SphK1 and SphK2. Both forms catalyze the synthesis of sphingosine 1-phosphate (S1P), a sphingolipid involved in ischemic
preconditioning (IPC). Since the ratio of SphK1&#x2009;:&#x2009;SphK2 changes dramatically with aging, it is important to assess the role of SphK2 in IR injury and IPC. Langendorff mouse hearts were subjected to IR (30&#x2009;min
equilibration, 50&#x2009;min global ischemia, and 40&#x2009;min reperfusion). IPC consisted of 2&#x2009;min of ischemia and 2&#x2009;min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), &#xb1;&#x2009;dP/dtmax, and heart rate between SphK2 null (KO)
and wild-type (WT) hearts. In KO hearts, SphK2 activity was undetectable, and SphK1 activity was unchanged compared to WT. Total SphK activity was reduced by 53&#x25;. SphK2 KO hearts subjected to IR exhibited significantly more cardiac damage (<svg style="vertical-align:-0.97874pt;width:36.962502px;" id="M1" height="10.8125" version="1.1" viewBox="0 0 36.962502 10.8125" width="36.962502" xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.8125)">
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				<tspan style="font-size: 11.21px; " x="23.861832" y="0">1</tspan>
			</text>

		</g>
	</g>
</svg>&#x25;
infarct size) compared with WT (<svg style="vertical-align:-0.97874pt;width:36.962502px;" id="M2" height="10.8125" version="1.1" viewBox="0 0 36.962502 10.8125" width="36.962502" xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.8125)">
		<g transform="translate(72,-63.35)">
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			</text>

		</g>
	</g>
</svg>&#x25; infarct size); postischemic recovery of LVDP
was lower in KO hearts. IPC exerted cardioprotection in WT hearts. The protective
effect of IPC against IR was diminished in KO hearts which had much higher infarction sizes (<svg style="vertical-align:-0.97874pt;width:36.962502px;" id="M3" height="10.9875" version="1.1" viewBox="0 0 36.962502 10.9875" width="36.962502" xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.9875)">
		<g transform="translate(72,-63.21)">
			<text transform="matrix(1,0,0,-1,-71.95,64.24)">
				<tspan style="font-size: 11.21px; " x="0" y="0">3</tspan>
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				<tspan style="font-size: 11.21px; " x="23.861832" y="0">2</tspan>
			</text>

		</g>
	</g>
</svg>&#x25;) compared to the IPC/IR group in control hearts (<svg style="vertical-align:-0.97874pt;width:36.962502px;" id="M4" height="10.8125" version="1.1" viewBox="0 0 36.962502 10.8125" width="36.962502" xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.8125)">
		<g transform="translate(72,-63.35)">
			<text transform="matrix(1,0,0,-1,-71.95,64.37)">
				<tspan style="font-size: 11.21px; " x="0" y="0">1</tspan>
				<tspan style="font-size: 11.21px; " x="5.6040001" y="0">2</tspan>
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				<tspan style="font-size: 11.21px; " x="23.861832" y="0">1</tspan>
			</text>

		</g>
	</g>
</svg>&#x25;). Western analysis revealed that KO
hearts had substantial levels of phosphorylated p38 which could predispose the
heart to IR injury. Thus, deletion of the SphK2 gene sensitizes the myocardium to IR injury and
diminishes the protective effect of IPC.

Donald A. Vessey

Luyi Li

Zhu-Qiu Jin

Michael Kelley

Norman Honbo

Jianqing Zhang

Joel S. Karliner

A Sphingosine Kinase Form 2 Knockout Sensitizes Mouse Myocardium to Ischemia/Reoxygenation Injury and Diminishes Responsiveness to Ischemic Preconditioning

Degradation of oxidized or oxidatively modified proteins is an essential part of the antioxidant defenses of cells. 4-Hydroxy-2-nonenal, a major reactive aldehyde formed by lipid peroxidation, causes many types of cellular damage. It has been reported that 4-hydroxy-2-nonenal-modified proteins are degraded by the ubiquitin-proteasome pathway or, in some cases, by the lysosomal pathway. However, our previous studies using U937 cells showed that 4-hydroxy-2-nonenal-modified glyceraldehyde-3-phosphate dehydrogenase is degraded by cathepsin G. In the present study, we isolated the 4-hydroxy-2-nonenal-modified glyceraldehyde-3-phosphate dehydrogenase-degrading enzyme from rat neutrophils to an active protein fraction of 28&#x2009;kDa. Using the specific antibody, the 28&#x2009;kDa protein was identified as cathepsin G. Moreover, the degradation activity was inhibited by cathepsin G inhibitors. These results suggest that cathepsin G plays a crucial role in the degradation of 4-hydroxy-2-nonenal-modified glyceraldehyde-3-phosphate dehydrogenase.

Yukihiro Tsuchiya

Go Okada

Shigeki Kobayashi

Toshiyuki Chikuma

Hiroshi Hojo

4-Hydroxy-2-Nonenal-Modified Glyceraldehyde-3-Phosphate Dehydrogenase Is Degraded by Cathepsin G in Rat Neutrophils

About this journal

Oxidative Medicine and Cellular Longevity publishes research involving cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, and metabolism.

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Chief Editor&nbsp;Dr Vasquez-Vivar has experience in free radical and redox biology research including the discovery of the role of tetrahydrobiopterin in the regulation of superoxide generation by endothelial and neuronal nitric oxide synthase.

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Oxidative Medicine and Cellular Longevity - Table of contents 2011

Oxidative Medicine and Cellular Longevity | Hindawi

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Oxidative Medicine and Cellular Longevity publishes research involving cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, and metabolism.

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Oxidative Medicine and Cellular Longevity

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Oxidative Medicine and Cellular Longevity