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

Abstract

Nonhuman primate models of Parkinson's disease (PD) have been invaluable to our understanding of the human disease and in the advancement of novel therapies for its treatment. In this review, we attempt to give a brief overview of the animal models of PD currently used, with a more comprehensive focus on the advantages and disadvantages presented by their use in the nonhuman primate. In particular, discussion addresses the 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydopyridine (MPTP), rotenone, paraquat, and maneb parkinsonian models. Additionally, the role of primate PD models in the development of novel therapies, such as trophic factor delivery, grafting, and deep brain stimulation, are described. Finally, the contribution of primate PD models to our understanding of the etiology and pathology of human PD is discussed.Key words: Parkinson's disease; Nonhuman primates; Animal models; Therapeutics PARKINSON'S DISEASEsymptoms have taken a backseat to the motor problems that most often define PD. Although the etiology of PD Societal Impact and Biological Features remains unclear, degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) has It has been estimated that over 1 million Americans are currently living with Parkinson' disease (PD) with been recognized as a primary pathology (82). Loss of DA neurons in the SN results in increased inhibition of an additional 40,000 persons in the US diagnosed each year, producing an estimated annual cost of greater than excitatory output from the thalamus to the motor cortex, causing a generalized inhibition of both movement initi-$5.6 billion (88). While PD is often considered a disease of the elderly and age is clearly the most powerful risk ation and execution. Histology of nigral tissue from PD patients shows decreased numbers of DA neurons and factor, many patients have an early onset. In this regard, it is significant that approximately 15% of patients are the presence of Lewy bodies, intracellular inclusions, in remaining neurons. Degeneration of SNpc is associated diagnosed before the age of 50 (88).In its classical description, PD is a neurodegenerative with aberrant neuronal plasticity and molecular signaling within the basal ganglia, resulting in a chronic imdisorder affecting primarily movement, muscle control, and balance. Diagnostic hallmarks of PD include cogbalance of insufficient DA levels, aggravated by unregulated cholinergic and glutamatergic signaling (82). wheel rigidity, resting tremor, bradykinesia, masked faces, stooped posture, and shuffling gait (88). NonmoPatients are typically asymptomatic until greater than 60% of the DA cell number is lost from the substantia tor symptoms such as dementia, depression, constipation, pain, and sleep disturbances are serious unmet nigra (88). Therefore, a critical component in effectively treating the nigrostriatal pathology in PD will necessitate needs of PD patients. Scientifically, these nonmotor

Enhancement of Striatal Dopaminergic Function Following Autologous Neural Cell Ecosystems (ANCE) Transplantation in a Non-Human Primate Model of Parkinson’s Disease

“…Furthermore, spontaneous motion activity data in Mk-LL were not dramatically different from the other monkeys (Mk-MY and Mk-MI: Figure 3), which is consistent with the observation that all three monkeys exhibited a comparable striatal 18F-DOPA uptake drop following MPTP lesioning ( Figure 4A). Although it has been reported that stable motor deficits occur in case of striatal dopaminergic depletion of at least 80% [51], a more reliable correlation between motor symptoms and dopaminergic depletion may require the acquisition of a vast palette of motor parameters in order to assess distinct motor attributes, which may be affected differently by graded dopaminergic depletions. The discrepancy observed in the present study between clinical score and spontaneous motion activity data appears in contradiction with a previous report [49] comparing these 2 parameters.…”

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

“…Following the discovery of GDNF, several studies demonstrated that GDNF protein, infused into the nigral region, is efficacious in reducing or preventing dopaminergic toxicity in rodent models of Parkinson's disease (Beck et al, 1995;Kearns et al, 1997;Tomac et al, 1995a;Soderstrom et al, 2006). In primate model of Parkinson's disease, GDNF protects dopaminergic neurons in the substantia nigra, maintains dopamine levels in striatum, and improves Parkinsonian symptoms (Gash et al, 1996;Costa et al, 2001;Slevin et al, 2005).…”

Driving GDNF expression: The green and the red traffic lights

“…GDNF is a promising therapeutic agent for the treatment of neurodegenerative diseases, in particular PD. In fact, many studies in animal models (reviewed by Soderstrom et al, 2006) and some studies in PD patients show that GDNF delivery can have trophic effects and restore motor function (Gill et al, 2003;Slevin et al, 2005), although some problems need to be overcome before GDNF therapy for PD becomes a reality (Sherer et al, 2006). For instance, the delivery of GDNF to the central nervous system (CNS) is challenging because GDNF is unable to cross the blood-brain barrier (Kastin et al, 2003;Kirik et al, 2004).…”