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The anticholinesterase drug tacrine (Tac) is known to have a beneficial effect on memory deficit in mice involving in the process the cholinergic system in the brain. Chemically induced kindling is a well-known model of petit mal epilepsy. Kindling develops after repeated administration of subconvulsant doses of pentylenetetrazole (PTZ). This model is suitable for studying the two CNS disturbances associated with epilepsy, i.e. seizure attacks and memory impairment. OBJECTIVE. The aim of the present study was to examine the effect of the anticholinesterase drug Tac on the model of PTZ kindling and on active avoidance in mice. METHODS. Kindling was induced by repeated administration of PTZ (40 mg/kg) s.c. at 48-hour intervals. Tac (at doses of 0.1, 0.5 and 1 mg/kg) was injected 40 minutes before PTZ over an 8 - week period in 4 experimental groups of mice. Seizure intensity was scored using a 5-grade scale. Kindling was defined as 3, 4 or 5 grade seizures evoked by 3 consecutive doses of PTZ and treatment was discontinued. The active avoidance method (training session consisting of 50 trials) was used to test learning and memory functions. On day 7 following the learning session a memory retention test was performed. The challenge dose of PTZ was given after a 15-day discontinuation of treatment.In control mice, kindling was developed over a 7-week period of treatment. Mice injected with Tac (in 3 consecutive doses) showed increased seizure intensity from week 1 through week 7 of the study. On learning and memory retention tests kindled mice showed a reduced learning capabilities whereas a statistically significant upward tendency in the number of conditioned responses (avoidances) was recorded in mice treated with Tac (1 mg/kg), when compared with the controls. Mice treated with Tac (in doses of 0.1 and 0.5 mg/kg) also exhibited an increased number of avoidances on learning and memory retention tests.1. The anticholinesterase drug Tac increased the seizure intensity and facilitated the development of PTZ kindling in mice. 2. On the basis of well-developed kindling Tac did not impair the memory of the experimental animals, which is possibly due to its CNS stimulating effect.

Protein-DNA interactions were studied in vivo at the region containing a human DNA replication origin, located at the 3' end of the lamin B2 gene and partially overlapping the promoter of another gene, located downstream. DNase I treatment of nuclei isolated from both exponentially growing and nonproliferating HL-60 cells showed that this region has an altered, highly accessible, chromatin structure. High-resolution analysis of protein-DNA interactions in a 600-bp area encompassing the origin was carried out by the in vivo footprinting technique based on the ligation-mediated polymerase chain reaction. In growing HL-60 cells, footprints at sequences homologous to binding sites for known transcription factors (members of the basic-helix-loop-helix family, nuclear respiratory factor 1, transcription factor Sp1, and upstream binding factor) were detected in the region corresponding to the promoter of the downstream gene. Upon conversion of cells to a nonproliferative state, a reduction in the intensity of these footprints was observed that paralleled the diminished transcriptional activity of the genomic area. In addition to these protections, in close correspondence to the replication initiation site, a prominent footprint was detected that extended over 70 nucleotides on one strand only. This footprint was absent from nonproliferating HL-60 cells, indicating that this specific protein-DNA interaction might be involved in the process of origin activation.