Chronic treatment (2 weeks) with piracetam (500 mg/kg, once daily PO) elevated m-cholinoceptor density in the frontal cortex of aged (18 months) female mice by about 30-40%, but had no effect on m-cholinoceptor density in the frontal cortex of young (4 weeks) mice. The effect of piracetam on m-cholinoceptor density as determined by the specific binding of tritiated QNB was not affected by concomitant daily treatment with either choline (200 mg/kg) or scopolamine (4 mg/kg). It is concluded that the effect of piracetam on m-cholinoceptor density could explain the positive effects which have been reported for combinations of cholinergic precursor treatment with piracetam on memory and other cognitive functions in aged experimental animals and patients and could also represent part of the possible mechanism of action of piracetam alone.
A doxorubicin-resistant human bladder carcinoma cell line RT112/D21 was established by continuous exposure of the parental line RT112 to increasing concentrations of doxorubicin over a period of 9 months. RT112/D21 cells expressed significantly more P-170 glycoprotein than the parental line, and rhodamine 123 efflux, as a functional parameter of P-170 glycoprotein activity, was increased. RT112/D21 cells were 96 times more resistant to doxorubicin than RT112 cells, and cross-resistance to epirubicin and vinblastine was present. Sensitivity to methotrexate and mitomycin C remained unchanged. R-verapamil reversed resistance to doxorubicin, epirubicin and vinblastine in RT112/D21 cells but did not affect sensitivity to methotrexate and mitomycin C. In RT112 cells, R-verapamil had no effect on drug sensitivity. Thus, it may be assumed that primary or induced MDR1 gene-encoded P-170 glycoprotein expression is a relevant mechanism of chemoresistance in transitional cell carcinoma, and that chemotherapeutic strategies in combination with chemosensitizers improve response rates.
Chronic treatment (2 weeks) with either scopolamine (4 mg/kg, once daily p.o.) or choline (200 mg/kg, once daily p.o.) resulted in a pronounced muscarinic cholinergic receptor up- or down-regulation in the frontal cortex of young (4 weeks) but not of aged (18 months) female mice. It is speculated that a similar age-related decline of muscarinic receptor plasticity might contribute to the profound dysfunction of cholinergic neurotransmission in Alzheimer's disease.
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