Sensorimotor deficits in a unilateral intrastriatal 6-OHDA partial lesion model of Parkinson's disease in marmoset monkeys

Abstract

Animal studies investigating the efficacy of neurotrophic factors as treatments for Parkinson's disease (PD) ideally require partial dopamine (DA) lesion models. The intrastriatal 6-hydroxydopamine (6-OHDA) lesion model may be suitable for this purpose. Although this model has been well characterized in rodents, it has not previously been used in monkeys. The goal of the present study was to characterize the behavioral effects of unilateral injections of 6-OHDA in the basal ganglia of common marmoset monkeys (Callithrix jacchus). Cell counts from tyrosine hydroxylase immunochemistry 5 months postlesion revealed DA cell loss in the substantia nigra on the lesioned side to approximately 46% of relative to the unlesioned side. 6-OHDA lesioned monkeys showed a variety of behavioral deficits. Apomorphine induced rotation and simple sensorimotor measures (head position bias and PD disability rating score) were most affected by the lesion. The largest deficits were seen at 1 or 2 weeks postsurgery but had recovered by week 10. 6-OHDA lesioned monkeys took longer to complete a more complex sensorimotor staircase task. At 3.5 months postlesion, 6-OHDA monkeys also showed deficits on an object retrieval task designed to measure sensorimotor planning and skilled hand use. alpha-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, reinstated those deficits which had undergone recovery in the lesioned animals and also exacerbated the deficits on the staircase task. This model has potential in assessing treatments for PD aimed at curtailing disease progression such as continuous delivery of neurotrophic factors.

Continuous Low-Level Glial Cell Line-Derived Neurotrophic Factor Delivery Using Recombinant Adeno-Associated Viral Vectors Provides Neuroprotection and Induces Behavioral Recovery in a Primate Model of Parkinson's Disease

“…The injections were made using coordinates derived from the stereotaxic atlas of Stephan et al (1980) at the following sites: (1) In experiment 2, the monkeys in group GDNF plus LES and group GFP plus LES underwent the intrastriatal 6-OHDA surgery 8 weeks after the vector surgery. In a previous study, we found that nine intrastriatal injections of 8 g each of 6-OHDA resulted in behavioral deficits that recovered by 10 weeks after lesion (Eslamboli et al, 2003a). In the hope of achieving longer-lasting behavioral deficits, twice as many injections were made into the striatum between coordinates AP6.5 to AP13.5, LAT2.3 to LAT6.7, and V8.5 to V13.2 (i.e., a total of 18 injections of 8 g each of 6-OHDA).…”

“…GDNF expression at 0.04 ng/mg of tissue did not affect normal DA neurotransmission, so an rAAV expressing this amount was used in a recently developed intrastriatal 6-hydroxydopamine (6-OHDA) lesion (LES) model of PD in monkeys (Eslamboli et al, 2003a). This low level of GDNF expression in the striatum provided substantial protection of the nigrostriatal DA system and functional recovery on a range of behavioral measures.…”

Neural Repair Strategies for Parkinson's Disease: Insights from Primate Models

“…Following unilateral these novel therapies will be discussed in more detail later in this review. lesions, asymmetrical rotation can be observed spontaneously in rats, or in response to dopaminergic drugs 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine such as amphetamine, apomorphine, and levodopa (30,52). This rotational analysis has been important for the First discovered to produce parkinsonian effects in human drug users (63), 1-methyl-4-phenyl-1,2,3,6-tetrabehavioral quantification of lesion severity as well as providing a measurement of therapy-induced recovery.…”

A simple method for assessing muscle function in common marmosets

“…Figure 5 Maximum weight pulled by individual female and male marmosets relative to body weight during baseline period Eslamboli et al 2003) rather than measuring muscle function per se.…”

“…As well as investigating toxicological effects of compounds on muscle function, the technique has potential to improve the characterization of marmoset models of human disease. These could include models of Parkinson's disease (Henderson et al 1998, Eslamboli et al 2003), Huntington's disease (Kendall et al 2000) and the muscle-weakening effects of stroke (Marshall et al 2000) and could, of course, be scaled up for applications using larger species of non-human primates.…”