Osama M. Abo-Salem

GlyR α3: An Essential Target for Spinal PGE2-Mediated Inflammatory Pain Sensitization

Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR α3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR α3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR α3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR α3 may provide a previously unrecognized molecular target in pain therapy.

Hesperidin, an antioxidant flavonoid, prevents acrylonitrile-induced oxidative stress in rat brain

Acrylonitrile (ACN) is a volatile, toxic liquid used as a monomer in the manufacture of synthetic rubber, styrene plastics, acrylic fiber, and adhesives. ACN is a potent neurotoxin. A role for free radical mediated lipid peroxidation in the toxicity of ACN has been suggested. We examined the ability of hesperidin, an antioxidant flavonoid, to attenuate ACN‐induced alterations in lipid peroxidation in rat brains. The daily oral administration of ACN to male albino rats in a dose of 50 mg/kg bwt for a period of 28 days produced a significant elevation in brain lipid peroxides measured as malondialdehyde (MDA) amounting to 107%, accompanied by a marked decrease in brain‐reduced glutathione (GSH) content reaching 63%. In addition, ACN administration resulted in significant reductions in the enzymatic antioxidant parameters of brain; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px), and glutathione‐S‐transferase (GST) recording 43%, 64%, 52%, and 43%, respectively. On the other hand, pretreatment with hesperidin and its coadministration with ACN once daily in a dose of 200 mg/kg bwt i.p. for 28 days ameliorated ACN‐induced alterations in brain lipid peroxidation. These results suggest that hesperidin may have a beneficial role against ACN‐induced oxidative stress in the brain; an effect that is mainly attributed to the antioxidant property of hesperidin.

Hepatoprotective activity of quercetin against acrylonitrile‐induced hepatotoxicity in rats

Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical‐mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile‐induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile‐induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile‐induced hepatotoxicity through its antioxidant activity.

The protective effect of aminoguanidine on doxorubicin-induced nephropathy in rats.

Reactive oxygen species and cytokines have been implicated in the nephrotoxicity induced by doxorubicin. The goal of the present study was to determine protective effect of aminoguanidine on doxorubicin‐induced nephrotoxicity in rats. Different groups of male Wistar rats received doxorubicin (67.75 mg/kg/i.p./2 days), aminoguanidine alone and aminoguanidine (200 and 400 mg/kg/i.p./30 days) prior to doxorubicin, respectively. Doxorubicin significantly increased serum creatinine (505%), blood urea nitrogen (333%), nitric oxide (406%), and plasma tumor necrosis factor‐alpha (706%) as well as urinary albumin (452%) and N‐acetyl‐β‐d‐glucosaminidase (415%) compared to control. Moreover, renal glutathione (334%), superoxide dismutase (283%), and catalase (513%) were significantly reduced accompanied with elevation in renal malondialdehyde compared to control. Pretreatment with aminoguanidine mitigated such changes in all mentioned parameters. Histopathological changes showed that doxorubicin‐caused significant structural damages to kidneys that were reduced with aminoguanidine. Results indicate that reactive oxygen species and cytokines are involved in doxorubicin‐induced nephrotoxicity, which can be reduced by aminoguanidine.

Potential testicular toxicity of sodium nitrate in adult rats

Nitrate is a common contaminant in groundwater aquifers. Current study aimed at evaluating the potential testicular toxicity of sodium nitrate in rats. Sodium nitrate was given orally to rats at doses of 50, 100 or 200 mg/kg/day for 60 consecutive days. Sperm count and motility, daily sperm production and testis weight were significantly decreased specially at high doses. Testicular activity of lactate dehydrogenase-X, glucose-6-phosphate dehydrogenase, and acid phosphatase were inhibited in a dose-related manner. Lipid peroxides and hydrogen peroxide production were significantly increased in all treated animals. This was accompanied by inhibition of testicular activities of superoxide dismutase and glutathione peroxidase. Fifty mg/kg of sodium nitrate did not significantly alter catalase or glutathione reductase activity. Glutathione was significantly decreased by sodium nitrate in a dose-related manner. The decrease in sperm count and motility and daily sperm production was confirmed by histopathological studies which indicated chromatolysis, pyknosis and necrosis in spermatocytes. In conclusion, subchronic exposure of rats to sodium nitrate results in testicular toxicity as evidenced by decreased sperm count and motility, daily sperm production and testis weight, inhibited activity of enzyme markers of spermatogenesis and induction of histopathological changes. These effects are attributed, at least partly, to testicular oxidative stress.

Visceral, inflammatory and neuropathic pain in glycine receptor alpha 3-deficient mice.

The &agr;3-subunit of strychnine-sensitive glycine receptors is an important modulator of the pain-sensitizing effects of spinal prostaglandin prostaglandin E2. Mice deficient for &agr;3-subunit of strychnine-sensitive glycine receptors lack the prostaglandin E2-induced inhibition of glycinergic neurotransmission and recover faster from inflammation-induced hyperalgesia. It, however, remains unclear whether &agr;3-subunit of strychnine-sensitive glycine receptors plays a role in other pain models involving prostaglandin synthesis, such as chemically induced pain or neuropathic pain. In this paper, we show a reduction of acetic acid-induced writhing responses in the absence of &agr;3-subunit of strychnine-sensitive glycine receptors, but no changes in formalin-induced pain. Furthermore, &agr;3-subunit of strychnine-sensitive glycine receptors-deficient mice develop normal thermal hyperalgesia and tactile allodynia. Thus, &agr;3-subunit of strychnine-sensitive glycine receptors is involved in the modulation of moderate inflammatory acetic acid-induced pain responses, but neither in formalin-induced pain nor in neuropathic pain.

Curcumin Ameliorates Streptozotocin-Induced Heart Injury in Rats

Heart failure (HF) is one of diabetic complications. This work was designed to investigate the possible modulatory effect of curcumin against streptozotocin‐induced diabetes and consequently HF in rats. Rats were divided into control, vehicle‐treated, curcumin‐treated, diabetic‐untreated, diabetic curcumin–treated, and diabetic glibenclamide–treated groups. Animal treatment was started 5 days after induction of diabetes and extended for 6 weeks. Diabetic rats showed significant increase in serum glucose, triglycerides, total cholesterol, low‐density lipoprotein‐cholesterol, very low density lipoprotein‐cholesterol, nitric oxide, lactate dehydrogenase, cardiac malondialdehyde, plasma levels of interleukin‐6, and tumor necrosis factor‐alpha, and also showed marked decrease in serum high‐density lipoprotein‐cholesterol, cardiac reduced glutathione, and cardiac antioxidant enzymes (catalase, superoxide dismutase, and glutathione‐S‐transferase). However, curcumin or glibenclamide treatment significantly mitigated such changes. In conclusion, curcumin has a beneficial therapeutic effect in diabetes‐induced HF, an effect that might be attributable to its antioxidant and suppressive activity on cytokines.

Effect of lead toxicity on coenzyme Q levels in rat tissues

Lead is a persistent and common environmental contaminant, which chiefly plays a significant role in modern industry. Coenzyme Q acts as electron and proton carrier in mitochondria and functions as an antioxidant in its reduced form (ubiquinol). To investigate the hazardous effects of lead on the coenzyme Q level, rats were injected i.p. with lead acetate (5 mg/kg b.wt. daily for 6 weeks). Our results showed that the levels of both oxidized (ubiquinone) and reduced (ubiquinol) forms of coenzyme Q(9) and Q(10) in serum, brain, liver and kidney of lead-treated rats are quite different depending on the organ tissue type.

Erythrocyte nitric oxide synthase as a surrogate marker for mercury-induced vascular damage: The modulatory effects of naringin

In this study, endothelial nitric oxide synthase activity and nitric oxide (NO) production by human erythrocytes in the presence and absence of mercuric chloride (HgCl2), L‐arginine (L‐ARG), N ω ‐ nitro‐L‐arginine methyl ester (L‐NAME), and naringin (NAR) were investigated. In addition, the levels of reduced glutathione (GSH) and related enzymes were estimated in erythrocytes hemolysate. The protein carbonyl content (PCC) and thiobarbituric acid‐reactive substances (TBARS) levels were also determined. The results of this study revealed that the treatment of erythrocytes with either HgCl2 or L‐NAME induced a significant decrease in NOS activity and nitrite levels compared with control cells. Furthermore, mercury exposure significantly increased the levels of PCC and TBARS but reduced the GSH level. The activities of glucose‐6‐phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and glutathione‐S‐transferase (GST) were inhibited. The exposure of erythrocytes to HgCl2 in combination with L‐ARG, NAR, or both ameliorated the investigated parameters compared with erythrocytes incubated with HgCl2 alone. These results indicate that mercury exposure decreased both erythrocyte NOS activity and nitrite production, and that these parameters might be indicative of mercury exposure. The data also suggest that concomitant treatment with NAR can restore NO bioavailability through either its metal‐chelating properties or its antioxidant activity.