Browsing by Author "Breitinger, Hans-Georg"

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    In vivo protection against strychnine toxicity in mice by the glycine receptor agonist ivermectin
    (Hindawi, 2014) Maher, Ahmed; Radwan, Rasha; Breitinger, Hans-Georg
    The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin.
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    Overexpression of NMDAR2B in an inflammatory model of Alzheimer's disease: modulation by NOS inhibitors
    (Elsevier, 2014) Maher, Ahmed; Salah-Eldine El-Sayed, Nesrine; Breitinger, Hans-Georg; Zakaria Gad, Mohamed
    Background:Alzheimer’sdisease (AD)is a commonformof age-relateddementia, characterizedbydeposition of amyloid A plaques, neuroinflammation and neurodegeneration. N-methyl-d-aspartate receptors (NMDAR) are postsynaptic glutamate receptors that play a role in memory formation and are targets for memantadine, an anti-AD drug. Nitric oxide (NO) signaling has been involved in both memory development through neuronal NO synthase (nNOS), and neuroinflammation through inducible NO synthase (iNOS) which mediates CNS inflammatory processes. Aim: To study the expression of the NMDAR2B subunit in an inflammatory model of AD before and after treatment with NO modulators. Materials and methods: AD was induced in mice by a single dose of lipopolysaccharide (LPS). Behavioral tests for spatial and non-spatial memories and locomotor activity were performed to assess disease severity and progression. The effects of l-NAME (general NOS inhibitor), 1400W (iNOS inhibitor), diflunisal (systemic anti-inflammatory drug that does not cross the blood brain barrier), and l-arginine, the substrate for NOS was determined. Immunohistochemistry was done to confirm AD and brain lysates were tested for A formation, levels of NMDAR2B subunits, and brain NO levels. Results: Systemic LPS induced AD, as shown by cognitive impairment; increased levels of A and concomitant increase in the brain NO concentrations. This was associated with overexpression of NMDAR2B. All tested drugs improved behavioral dysfunction, prevented A formation and NMDAR overexpression, and lead to decrease in NO concentration in the brain. l-Arginine alone, however, did not produce similar improvements. Conclusion: NMDAR2B subunits are overexpressed in an inflammatory model of AD and NO inhibitors ameliorate this expression.