**7. Future directions for PD therapy**

Five relatively new approaches in anti-inflammatory therapy described above all show some promise for short-term or long-term therapeutics in PD. The use of exogenous antiinflammatory cytokines such as IL10 or TGFβ1, has been shown to have potent effects in reducing neurotoxicity in both *in vitro* and in animal models of PD. However, although both cytokines are considered to be predominantly anti-inflammatory, they each can have pro-inflammatory effects in certain contexts. More thorough functional studies are needed for these anti-inflammatory cytokines, especially in the context of PD models before these might be readily used in human therapy. Particularly important factors include what form and what mode of delivery will optimize the anti-inflammatory effects of the cytokines as therapy and ameliorate any unintended negative effects. Cell-based therapies such as regulatory T cells (Tregs) offer great promise for long-term therapy in many degenerative disorders including PD. Both the use of T cells and stem cell transplantation focus on regeneration as well as intervening in neuronal death processes. However, some of the

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#### **8. References**


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**0**

**18**

*USA*

**Mathematical Models: Interactions**

**Between Serotonin and Dopamine**

Janet Best1, Grant Oakley1, Michael Reed2 and H. Frederik Nijhout2

Parkinson's disease (PD) has traditionally been thought of as a dysfunction in the dopamine (DA) signaling system caused primarily by cell death in the substantia nigra pars compacta (SNc). However, strong evidence has been accumulating that the serotonin (5-HT) signaling system is also involved. First, 5-HT influences normal motor function through a dense innervation of the striatum. Second, substantial cell death of serotonergic neurons occurs in PD and in some cases may occur earlier than DA cell death. And, finally, there are indications that interactions between the 5-HT system and the DA system may be responsible for some of the symptoms of PD and some of the side effects of treatment by levodopa. Some of the

The 5-HT system is itself very complex. The serotonergic neurons in the raphe nuclei (RN) send ascending projections to a large number of different brain regions including medial prefrontal cortex (mPFC), motor cortex, hypothalamus, hippocampus, amygdala, and the basal ganglia. And, some of these brain regions, substantia nigra, amygdala, mPFC, and hypothalamus send projections back to the RN (Monti, 2010). Thus it is not surprising that 5-HT is linked to so many behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders (Feldman et al., 1997). Since the pharmacology and the electrophysiology of both the serotonergic and the dopaminergic systems are only partially understood, it is a daunting task to understand how these two systems affect one another. This is particularly true in the presence of a degenerative disease that involves massive cell

In this complicated situation, mathematical models can potentially provide insight into mechanisms and interactions. The purpose of the models is not to summarize what is already known. The purpose is to provide a platform for *in silico* biological experimentation. Using models one can try out ideas, validate or refute hypotheses, settle disputes in the literature, and sometimes discover new phenomena. Of course, to be useful the models have to be well-grounded in real physiology and the creation of such models is not easy. However, if one

**1. Introduction**

death in both systems.

evidence for these assertions is reviewed below.

**in Parkinson's Disease**

<sup>1</sup>*Ohio State University* <sup>2</sup>*Duke University*

