Two 2-Hydroxy-3-Alkyl-1,4-Naphthoquinones with In Vitro and In Vivo Activities against Toxoplasma gondii

Two 3-alkyl-substituted 2-hydroxy-1,4-naphthoquinones, NSC 113452 (NSC52) and NSC 113455 (NSC55), were evaluated for activity against Toxoplasma gondii in vitro and in murine models of acute toxoplasmosis. In vitro, both NSC52 and NSC55 significantly inhibited intracellular replication of T. gondii. In vivo, each compound was examined alone and in combination with other drugs currently used for treatment of human toxoplasmosis. Although none of the compounds protected mice against death when administered orally, both were significantly protective when administered intraperitoneally. In addition, a significant increase in survival was observed when suboptimal doses of each compound were used in combination with suboptimal doses of pyrimethamine or sulfadiazine. These results indicate that combinations of NSC52 or NSC55 with pyrimethamine or sulfadiazine have promising activity against T. gondii.     

Characterization of bioactive compounds and ameliorative effects of Ceratonia siliqua leaf extract against CCl4 induced hepatic oxidative damage and renal failure in rats

Ceratonia siliqua is a typical Mediterranean plant, mainly used in food and Tunisian traditional folk medicine. Among the tested extracts, the ethyl acetate fraction (EACs) exhibited the highest total phenolic and flavonoids content. The antioxidant activity in vitro systems showed a more significant potent free radical scavenging activity of this extract than other analysis fractions. The HPLC finger print of EACs active extract showed the presence of six phenolic compounds. The in vivo results showed that oral administration of CCl₄ enhanced levels of hepatic and renal markers (ALT, AST, ALP, LDH, γ-GT, urea and creatinine) in the serum of experimental animals. It also increased the oxidative stress markers resulting in increased levels of the lipid peroxidation with a concomitant decrease in the levels of enzymatic antioxidants (SOD, CAT, GPx) in both liver and kidney. The pre-treatment of experimental rats with 250 mg/kg (BW) of the EACs, by intraperitoneal injection for 8 days, prevented CCl₄ induced disorders in the levels of hepatic and kidney markers. The biochemical changes were in accordance with histopathological observations suggesting a marked hepatoprotective and nephroprotective effect of the EACs extract.     

Synthesis of 4-hydroxycoumarin heteroarylhybrids as potential antimicrobial agents

A new series of 4-hydroxycoumarin derivatives 3a-d was synthesized by the reaction of 3-bromo-4-hydroxy coumarin 1 with various heteroaldehydes 2a-d in good yields. The synthesized compounds were characterized on the basis of their elemental and spectral (IR, (1)H-NMR and mass spectrometry) analysis. All target compounds were evaluated for their in-vitro antimicrobial activity against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, and Escherichia coli bacterial strains and fungal cultures of Candida albicans, Aspergillus fumigatus, Trichophyton mentagrophytes, and Penicillium marneffei by disk diffusion assay with slight modifications. The minimum inhibitory concentration (MIC) was determined for the test compounds as well as for reference standards. Among the tested compounds, 3a has shown the most potent antibacterial as well as antifungal activities.     

Acute renal cortical necrosis due to acquired antiprotein S antibodies

Although varicella is a common disease of childhood, renal complications are quite rare. We report here the interesting case of a-22 month-old boy exhibiting renal cortical necrosis related to an acquired protein S deficiency following varicella. Ten days after the vesicle eruption appearance, he presented with ecchymosed heels, oligoanuric kidney failure, anemia [hemoglobin (Hb) 78 g/L], schizocytosis (2.5%), but normal platelet count. Kidney sonography and magnetic resonance imaging evoked renal cortical necrosis. All together, these features suggested acquired protein S deficiency secondary to varicella. Strikingly, it was confirmed by a dramatic decrease in protein S plasma activity and a huge increase in immunoglobulin (Ig)G antibodies against protein S in the plasma. Anticoagulation therapy in addition with plasmapheresis and steroid pulses allowed a dramatic decrease in the antibodies against protein S and recovery of normal protein S activity. Undelayed diagnosis and treatment did not avoid kidney insufficiency but prevented life-threatening complications. In the light of this case report, protein S deficiency due to antibody inhibition should be carefully monitored anytime in the context of varicella when kidney insufficiency or necrosis occurs.     

Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey

After injury, regrowth of axons in mammalian adult central nervous system is highly limited. However, in monkeys subjected to unilateral cervical lesion (C7-C8 level), neutralization of an important neurite outgrowth inhibitor, Nogo-A, stimulated axonal sprouting caudal to the lesion, accompanied by enhanced functional recovery of manual dexterity, compared with lesioned monkeys treated with a control antibody (Freund et al. [2006] Nat. Med. 12:790-792). The present study aimed at comparing the same two groups of monkeys for axonal sprouting rostral to the cervical lesion. The corticospinal tract was labeled by injecting the anterograde tracer biotinylated dextran amine into the contralesional motor cortex. The corticospinal axons were interrupted at the level of the lesion, accompanied by retrograde axonal degeneration (axon dieback), reflected by the presence of terminal retraction bulbs. The number of terminal retraction bulbs was lower in anti-Nogo-A antibody treated monkeys, and, when present, they were found closer to the lesion than in control-antibody treated monkeys. Compared with control antibody treated monkeys, the anti-Nogo-A antibody treated monkeys exhibited an increased cumulated axon arbor length and a higher number of axon arbors going in the medial direction from the white to the gray matter. Higher in the cervical cord (at C5 level), the anti-Nogo-A treatment enhanced the number of corticospinal fibers crossing the midline, suggesting axonal sprouting. Thus, the anti-Nogo-A antibody treatment enhanced axonal sprouting rostral to the cervical lesion; some of these fibers grew around the lesion and into the caudal spinal segments. These processes paralleled the observed improved functional recovery.     

Safety of endovascular treatment of intracranial aneurysms with a new,complex shaped Guglielmi detachable coil

Introduction The Guglielmi detachable coil (GDC) 360°, a new complex shaped bare platinum coil, became available in Europe for aneurysm treatment in September 2005. The purpose of this study was to assess the feasibility and safety of selective embolization of intracranial aneurysms with the GDC 360° in 52 consecutive patients. Methods All patients included in this study were registered in a prospectively maintained database. We assessed the patient clinical history, aneurysm shape and dimensions, technical details and complications of the procedures, degree of aneurysm occlusion, and clinical findings upon discharge. In all patients, the first coil deployed was a GDC 360°. Results Over a 6-month period, we intended to treat 52 aneurysms with the GDC 360° in 52 patients. Of these 52 patients, 42 (81%) were treated in the context of subarachnoid haemorrhage. In 51 of 52 patients, the underlying aneurysm was successfully treated by coil embolization. Six procedures (11.5%) were complicated by the formation of thrombus in the parent artery during the intervention. One patient suffered a stroke related to the procedure. Angiograms obtained immediately after the procedure showed complete occlusion of the aneurysmal sac in 38 of 51 procedures (74.5%), a neck remnant in 11 (21.6%), and a residual aneurysm in 2 (3.9%). In 43 of 51 patients (84.3%), clinical assessment demonstrated independent clinical status, whereas 7 patients (13.7%) required assistance in the activities of daily living upon hospital discharge. One patient (2.0%) died after development of a severe vasospasm 10 days after the endovascular procedure. Conclusion The GDC 360° can be safely used for the endovascular occlusion of intracranial aneurysms.     

Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice

Interleukin-1β (IL-1β) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1β neutralizing antibody IgG2a/k (1.5 μg/mL) or control antibody was infused at a rate of 0.25 μL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1–7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1β in vitro . IL-1β neutralization attenuated the CCI-induced cortical and hippocampal microglial activation ( P  <   0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils ( P  <   0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1β neutralization ( P  <   0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue ( P  <   0.05). In brain-injured animals, IL-1β neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits ( P  <   0.05) without influencing neurological motor function. Our results indicate that IL-1β is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.