Katherine E. Soderstrom

Neurotrophic factor therapy for Parkinson’s disease

Parkinsons 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.

Trophic factors therapy in Parkinson’s disease

Parkinsons disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.

The synaptic impact of the host immune response in a parkinsonian allograft rat model : Influence on graft-derived aberrant behaviors

Graft-induced dyskinesias (GIDs), side-effects found in clinical grafting trials for Parkinsons disease (PD), may be associated with the withdrawal of immunosuppression. The goal of this study was to determine the role of the immune response in GIDs. We examined levodopa-induced dyskinesias (LIDs), GID-like behaviors, and synaptic ultrastructure in levodopa-treated, grafted, parkinsonian rats with mild (sham), moderate (allografts) or high (allografts plus peripheral spleen cell injections) immune activation. Grafts attenuated amphetamine-induced rotations and LIDs, but two abnormal motor syndromes (tapping stereotypy, litter retrieval/chewing) emerged and increased with escalating immune activation. Immunohistochemical analyses confirmed immune activation and graft survival. Ultrastructural analyses showed increases in tyrosine hydroxylase-positive (TH+) axo-dendritic synapses, TH+ asymmetric specializations, and non-TH+ perforated synapses in grafted, compared to intact, striata. These features were exacerbated in rats with the highest immune activation and correlated statistically with GID-like behaviors, suggesting that immune-mediated aberrant synaptology may contribute to graft-induced aberrant behaviors.

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

Nonhuman primate models of Parkinsons 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.

Impact of Dendritic Spine Preservation in Medium Spiny Neurons on Dopamine Graft Efficacy and the Expression of Dyskinesias in Parkinsonian Rats

Dopamine deficiency associated with Parkinson’s disease (PD) results in numerous changes in striatal transmitter function and neuron morphology. Specifically, there is marked atrophy of dendrites and dendritic spines on striatal medium spiny neurons (MSN), primary targets of inputs from nigral dopamine and cortical glutamate neurons, in advanced PD and rodent models of severe dopamine depletion. Dendritic spine loss occurs via dysregulation of intraspine Cav1.3 L‐type Ca2+channels and can be prevented, in animal models, by administration of the calcium channel antagonist, nimodipine. The impact of MSN dendritic spine loss in the parkinsonian striatum on dopamine neuron graft therapy remains unexamined. Using unilaterally parkinsonian Sprague–Dawley rats, we tested the hypothesis that MSN dendritic spine preservation through administration of nimodipine would result in improved therapeutic benefit and diminished graft‐induced behavioral abnormalities in rats grafted with embryonic ventral midbrain cells. Analysis of rotational asymmetry and spontaneous forelimb use in the cylinder task found no significant effect of dendritic spine preservation in grafted rats. However, analyses of vibrissae‐induced forelimb use, levodopa‐induced dyskinesias and graft‐induced dyskinesias showed significant improvement in rats with dopamine grafts associated with preserved striatal dendritic spine density. Nimodipine treatment in this model did not impact dopamine graft survival but allowed for increased graft reinnervation of striatum. Taken together, these results demonstrate that even with grafting suboptimal numbers of cells, maintaining normal spine density on target MSNs results in overall superior behavioral efficacy of dopamine grafts.

Effect of levodopa priming on dopamine neuron transplant efficacy and induction of abnormal involuntary movements in parkinsonian rats

Clinical trials of neural grafting for Parkinsons disease (PD) have produced variable, but overall disappointing, results. One particular disappointment has been the development of aberrant motor complications following dopamine (DA) neuron grafting. Despite a lack of consistent benefit, the utility of dopamine neuron replacement remains supported by clinical and basic data. In a continued effort to elucidate factors that might improve this therapy, we used a parkinsonian rat model to examine whether pregraft chronic levodopa affected graft efficacy and/or graft‐induced dyskinesia (GID) induction. Indeed, all grafted PD patients to date have had a pregraft history of long‐term levodopa. It is well established that long‐term levodopa results in a plethora of long‐lasting neurochemical alterations and genomic changes indicative of altered structural and synaptic plasticity. Thus, therapeutic dopamine terminal replacement in a striatal environment complicated by such changes could be expected to lead to abnormal or inappropriate connections between graft and host brain and to contribute to suboptimal efficacy and/or postgraft GID behaviors. To investigate the effect of pregraft levodopa, one group of parkinsonian rats received levodopa for 4 weeks prior to grafting. A second levodopa‐naïve group was grafted, and the grafts were allowed to mature for 9 weeks prior to introducing chronic levodopa. We report here that, in parkinsonian rats, preexposure to chronic levodopa significantly reduces behavioral and neurochemical efficacy of embryonic dopamine grafts. Furthermore, dopamine terminal replacement prior to introduction of chronic levodopa is highly effective at preventing development of levodopa‐induced dyskinesias, and GID‐like behaviors occur regardless of pregraft levodopa status. J. Comp. Neurol. 515:15–30, 2009.

Animal Models of Parkinson’s Disease

Animal models have been critical to our study of Parkinson’s disease (PD). Models have historically been developed to replicate aspects of idiopathic PD pathology. Traditional models include the reserpine model, which replicates striatal dopamine depletion seen in PD, and the 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine environmental toxin models, that replicate PD’s nigral neurohistopathology. While invaluable to researchers, these models have limited ability to produce many important features of PD. Novel models, such as the rotenone, paraquat, and maneb environmental models, genetic models, the lipopolysaccharide model, and aged animal models have been recently developed as alternatives to traditional models.