Nonhuman Primate Models in Trophic Factor Research

Abstract

Nonhuman primates are essential experimental models for research dealing with trophic factors, particularly regarding the effects of these factors on higher cognitive functions, including memory. These animals have several advantages over rodents. First, these species are our closest relatives, and many features of nonhuman primate behavior and brain biology closely resemble those identified in humans. Second, available evidence indicates that the pharmacokinetics of psychotrophic drugs is similar between humans and monkeys—a major reason why monkeys are so popular in studies of behavioral pharmacology. Third, the clinical and pathological manifestations of naturally occurring or experimentally induced disorders in nonhuman primates resemble more closely the features of human disorders than do homologous disorders in nonprimate species. For example, although intoxication with l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes motoric abnormalities in mice associated with dysfunction of the nigrostriatal system (Chiueh et al., 1984; Hallman et al., 1984; Heikkila et al., 1984; Mayer et al., 1986; Gupta and Gupta,1988; Mori et al., 1988; Date et al., 1990), only primates, and especially the African green monkey, exhibit the full manifestations of Parkinsonism (Burns et al., 1983; Langston et al., 1984; Bankiewicz et al., 1986; LangstonJ987; DeLongl990). Similarly, although aged rats exhibit memory impairments (Gallagher and Burwell,1989; Markowska et al., 1989; Gallagher et al., 1990; Olton et al., 1991) and some alterations in certain populations of neurons in the brain (Hornberger et al., 1985; Luine et al., 1986; Mesulam et al., 1987; Fischer et al., 1989; Koh et al., 1989; Altavista et al., 1990), only aged monkeys develop the complex behavioral problems similar to those that occur in aged humans and, to a much greater extent, patients with Alzheimer’s disease (AD) (Price et al., 1991a). Thus, the more closely the behavioral and brain abnormalities resemble those that occur in humans, the greater the potential of the animal model for understanding processes relevant to human disease. The above reasons raise the question regarding to what extent primate models need to be examined before considering trophic factor therapies for human neurological diseases. For example, in the fall of 1989, an ad hoc committee convened at the National Institute on Aging to evaluate the potential of nerve growth factor (NGF) to treat certain symptoms of patients with AD (Phelps et al., 1989). This committee set a series of prerequisites to be met before small-scale NGF clinical trials could be considered. A major precondition included evidence of the efficacy of NGF on nonhuman primate models.