Neurotrophic factor therapy for Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative movement disorder for which there is currently no effective therapy. Over the past several decades, there has been a considerable interest in neuroprotective therapies using trophic factors to alleviate the symptoms of PD. Neurotrophic factors (NTFs) are a class of molecules that influence a number of neuronal functions, including cell survival and axonal growth. Experimental studies in animal models suggest that members of neurotrophin family and GDNF family of ligands (GFLs) have the potent ability to protect degenerating dopamine neurons as well as promote regeneration of the nigrostriatal dopamine system. In clinical trials, although no serious adverse events related to the NTF therapy has been reported in patients, they remain inconclusive. In this chapter, we attempt to give a brief overview on several different growth factors that have been explored for use in animal models of PD and those already used in PD patients.

Introduction

Parkinson’s disease (PD) is a common, progressive neurodegenerative disorder that affects approximately 1,000,000 Americans. PD is characterized by a gradual loss of dopamine (DA) neurons in the pars compacta region of the substantia nigra. In the healthy brain, these neurons send out axonal fibers which widely innervate neurons in the caudate and putamen and modulate basal ganglia activity via the synaptic release of DA. A significant loss of DA results in the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability (Bernheimer et al., 1973, Hornykiewicz and Kish, 1987, Parkinson’s Disease Foundation, 2009). While the pathology of PD is not limited to the nigrostriatal circuit, it has, to date, been the focus of most therapeutic interventions.

The motor symptoms of PD do not typically appear until 50% of the nigral DA neurons have been lost. Initially symptoms are mild and can be effectively treated with levodopa. However, as the disease progresses many patients show a gradual loss of levodopa efficacy, with oscillations in motor performance and the emergence of levodopa-induced dyskinesias. In an effort to impede or avoid these drug-related side-effects, the administration of levodopa is often delayed until later in the disease process with early symptoms being treated with DA agonists such as pramipexole, ropinirole, and pergolide. When the effectiveness of these drugs has diminished, levodopa treatment is then initiated with the hope that it will be effective in a more advanced patient. Alternative DA replacement strategies have demonstrated some efficacy, but most fail to address the progressive nature of DA neuronal loss and thus provide limited benefit. Surgical procedures, such as pallidotomy and deep brain stimulation, have also provided significant clinical benefits; however, like most means of DA replacement, none of these approaches have addressed the progressive nature of PD. Indeed, to date the available surgical or pharmacological therapies have not shown the ability to impede the progressive loss of DA neurons observed in PD. Therefore, there is a need for more effective long-lasting neuroprotective agents or restorative strategies to prevent degeneration of nigrostriatal neurons and axons and slow disease progression by preventing further DA loss.

In recent years, one strategy that has gained interest has been the application of trophic factors to affected regions in PD. Trophic factors are a class of neuroprotective compounds that can promote development, influence neuronal survival and axon growth, and modulate neuronal function. In 1951, Rita Levi-Montalcini and colleagues characterized the first nervous system growth factor, nerve growth factor (NGF) (Cohen and Levi-Montalcini, 1957, Levi-Montalcini and Hamburger, 1951). This discovery has been followed by decades of research resulting in the discovery and characterization of multiple different trophic factors. Currently, several putative nervous system growth factors have been identified and used to treat human diseases (e.g., Tuszynski, 1999). These factors possess a wide range of structures, receptor signaling mechanisms, target neurons, and biological effects.

In response to injury, many trophic factors and their receptors have been shown to increase in concentration, suggesting an endogenous regenerative response by these molecules (Hughes et al., 1999). Specific factors have been demonstrated to be potent neuroprotective agents for specific populations of neurons selectively affected in neurodegenerative diseases. Furthermore, these factors serve as neuroprotectant molecules against cytotoxic cell damage. They can act as anti-excitotoxins and antioxidants and, as such, have the capacity to enhance mitochondrial function. They have also been shown to upregulate calcium buffering proteins, antioxidant enzymes, and anti-apoptotic factors (Mattson, 1998). Based upon these properties, different trophic factors may be useful for treating a variety of neurological diseases.

Many studies have demonstrated the therapeutic effects of trophic factor delivery in PD. Multiple trophic factors have been shown to provide neuroprotection, neurorestoration, and functional improvement in a range of various PD animal models, as well as occasionally in clinical studies. In the following section, we address several different trophic factors that have been explored for use in PD, both in animal models and patients.