The effects of tetrahydroaminoacridine (THA), 3,4 diaminopyridine (3,4 DAP) and physostigmine were evaluated for their ability to reduce memory impairments in aged, test-sophisticated cebus monkeys (18 to 26 years old). Several doses of each drug were tested (PO) in each of ten different monkeys, allowing for direct and extensive comparison of each drug's efficacy in this model. The results of this comparative test revealed several potentially interesting findings: (1) all drugs produced improvement in a portion of the monkeys tested; (2) as in many past tests with aged monkeys and humans, wide variations in most effective dose, per subject, were observed; (3) different monkeys responded more effectively to one drug than another; and (4) under these tightly controlled conditions, physostigmine produced the most reliable and robust effects (p less than 0.005), in more monkeys, than did either THA (p less than 0.05) or 3,4 DAP (p less than 0.10).

4-Aminopyridine↗

PubMedDate not supplied

Lack of efficacy of clonidine on memory in aged cebus monkeys.

Using a dosing paradigm and an automated behavioral testing procedure designed to maximize potential drug efficacy, we evaluated the ability of clonidine to improve performance of aged monkeys on a trial-specific memory task. These results indicated that neither acutely administered (0.0025-0.04 mg/kg) or subchronically administered (0.01-0.06 mg/kg for 3 consecutive days) clonidine improved the performance of aged monkeys. These data are discussed in view of previously reported, conflicting data, as well as their implication regarding probable neurochemical factors involved in age-associated memory impairment and approaches to future palliative treatments.

Aging↗

PubMedDate not supplied

The need for common perspectives in the development and use of animal models for age-related cognitive and neurodegenerative disorders.

Research toward the development and use of animals models of age-related neurodegeneration and memory loss has accelerated rapidly during the past decade. However, the degree to which various investigators have been able to integrate their findings has not kept pace. Given the apparent complexity of neurodegenerative and cognitive phenomena, it seems essential that more effective dialogue between investigators with diverse backgrounds and approaches be achieved. Such a dialogue would likely reduce certain confusion and misunderstanding that currently exist in this field. It might also be expected that the dialogue would lead to the development of a working framework for continued growth and integration of novel findings and ideas. This paper attempts to promote a dialogue by identifying and discussing certain broad issues that produce unnecessary confusion in the common pursuit of using animals to understand various aspects of complex human neurodegenerative diseases. Also, some perspectives are suggested that may facilitate discussion and comparison of different animal models, independent of the paradigms and species used.

Aging↗

PubMedDate not supplied

Age differences in the vulnerability of facial recognition memory to proactive interference.

A facial recognition memory task was administered to 16 young subjects (age range 18-30) and 28 elderly subjects (age range 63-83). A continuous recognition paradigm was used, in which subjects were instructed to identify the repeated faces in an ongoing series of faces presented on a video monitor screen. A signal detection analysis of the data revealed a mild recognition memory deficit in the elderly, due mainly to an increase in false positives during the second half of the test session. This age-specific increase in late-session false alarms may be a result of increased sensitivity of the aged subjects to proactive interference from previously presented faces. Increasing the length of the delay between the initial and repeat presentation of a face decreased recognition accuracy in both groups, but the young subjects were more sensitive to the delay interval effect than the elderly. Multiple presentations of faces produced a comparable improvement in the recognition accuracy of both young and old subjects. The elderly subjects exhibited a more liberal response bias than the young subjects, indicating that impaired memory task performance of the aged subjects cannot be attributed to a more conservative test-taking strategy.

Adolescent↗

PubMedDate not supplied

Biocompatibility of poly (DL-lactide-co-glycolide) microspheres implanted into the brain.

The delivery of therapeutic molecules to the brain has been limited in part due to the presence of the blood-brain barrier. One potential solution is the implantation of biodegradable polymers with sustained release of drugs. Poly (DL-lactide-co-glycolide) (PLG) is a bioerodible polymer with a long and successful history of use as a suture material. More recently, PLG has been investigated for localized and sustained delivery of molecules into both peripheral sites and the brain. Despite its well-defined safety profile for parenteral applications, little information exists concerning the safety of PLG when implanted into the brain. To further characterize the biocompatibility of PLG in the brain, we examined the gliotic response following implants of PLG into the brains of rats. As a control, each animal received an injection of the suspension medium into the contralateral hemisphere. Following implantation, PLG was well tolerated. GFAP-positive astrocytes were observed throughout the cerebral cortex and striatum on both the implanted and control sides, with the reaction being greatest within the heavily myelinated fiber tracts of the corpus callosum. Quantitative analyses revealed that this reaction occurred within 1 h postsurgery, reached its peak at 1 week following surgery, and then decreased markedly by 1 month postsurgery. A minimal gliotic reaction was still present 1 year postsurgery but was localized to the needle tract. No differences in GFAP reactivity were seen between the polymer-implanted and control sides at any time point. Histological analysis determined that the majority of the PLG disappeared between 1 and 4 weeks. A set of parallel studies in which PLG samples were retrieved from the brain at various time points corroborated these findings and determined that the majority of PLG degraded within 2 weeks following implantation. Together, these results demonstrate that PLG is well tolerated following implantation into the CNS and that the astrocytic response to PLG is largely a consequence of the mechanical trauma that occurs during surgery. The biocompatibility of PLG implanted into the CNS provides further support for its use in a wide range of new therapeutic applications for sustained and localized drug delivery to the brain.

Animals↗