A major challenge in developing disease altering therapeutics for the treatment of Parkinson’s disease (PD) has been the delivery of compounds across the blood-brain barrier (BBB) to the central nervous system (CNS). While direct surgical infusion has been utilized to deliver compounds to the brain that don’t cross the BBB, issues of poor biodistribution in the CNS due in part to properties of the molecules being delivered and/or infusion device protocols have limited the widespread success of this invasive approach. To avoid the issues of surgically delivering compounds to the CNS, numerous studies have examined the use of intranasal administration as a non-invasive delivery method. The data presented in this dissertation examines intranasal administration of dopamine neuron stimulating peptide-11 (DNSP-11), a small, amidated peptide with neuroprotective and restorative properties, and its effects on the nigrostriatal system in animal models of PD. Here we demonstrate that severely lesioned 6-hydroxydopamine (6-OHDA) F344 rats repeatedly administered DNSP-11 intranasally exhibited a decrease in damphetamine- induced rotation, dopamine (DA) turnover, and an increase in tyrosine hydroxylase positive neuronal sparing. Additionally, tracer studies indicated rapid distributed throughout the CNS and CSF following a one-time bilateral intranasal dose of 125I-labeled DNSP-11. These results demonstrate that DNSP-11 can be delivered to the CNS intranasally, and maintains its neuroactive properties on the nigrostriatal system in a rat model of PD. In a dose escalation study of DNSP-11, we evaluated the efficacy of repeated intranasal administration in awake, vertically chaired trained, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) hemiparkinsonian rhesus macaques using an atomizer system over a 10-week period. Here we report that animals did not exhibit observable adverse effects at the DNSP-11 concentrations examined, bilateral increases in fine motor performance of the upper limbs, and changes in tissue levels of DA and its metabolites. Finally, tracer studies indicated signal present throughout the CNS and CSF following a one-time bilateral intranasal dose of 125I-labeled DNSP-11. These studies support the efficacy of the repeated intranasal administration of DNSP-11 in awake Rhesus macaques over 10-weeks, while also enhancing motor performance and striatal neurochemistry in a non-human primate model of PD.

<p>Deep brain stimulation (DBS) is used to treat the motor symptoms of advanced Parkinson's disease (PD). Although this therapy has been widely applied, the mechanisms of action underlying its effectiveness remain unclear. The goal of this dissertation was to investigate the mechanisms underlying the effectiveness of subthalamic nucleus (STN) DBS by quantifying changes in neuronal activity in the basal ganglia during both effective and ineffective DBS.</p><p>Two different approaches were adopted in this study. The first approach was the unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model. Using this animal model, we developed behavioral tests that were used to quantify the effectiveness of DBS with various frequencies and temporal patterns. These changes in behavior were correlated with changes in the activity of multiple single neurons recorded from the globus pallidus externa (GPe) and substantia nigra reticulata (SNr). The second approach was a computational model of the basal ganglia-thalamic network. The output of the model was quantified using an error index that measured the fidelity of transmission of information in model thalamic neurons. We quantified changes in error index as well as neural activity within the model GPe and globus pallidus interna (GPi, equivalent to the SNr in rats).</p><p>Using these two approaches, we first quantified the effects of different frequencies of STN DBS. High frequency stimulation was more effective than low frequency stimulation at reducing motor symptoms in the rat, as well as improving the error index of the computational model. In both the GPe and SNr/GPi from the rat and computational model, pathological low frequency oscillations were present. These low frequency oscillations were suppressed during effective high frequency DBS but not low frequency DBS. Furthermore, effective high frequency DBS generated oscillations in neural firing at the same frequency of stimulation. Such changes in neuronal firing patterns were independent of changes in firing rates.</p><p>Next, we investigated the effects of different temporal patterns of high frequency stimulation. Stimulus trains with the same number of pulses per second but different coefficients of variation (CVs) were delivered to the PD rat as well as PD model. 130 Hz regular DBS was more effective than irregular DBS at alleviating motor symptoms of the PD rat and improving error index in the computational model. However, the most irregular stimulation pattern was still more effective than low frequency stimulation. All patterns of DBS were able to suppress the pathological low frequency oscillations present in the GPe and SNr/GPi, but only 130 Hz stimulation increased high frequency 130 Hz oscillations. Therefore, the suppression of pathological low frequency neural oscillations was necessary but not sufficient to produce the maximum benefits of DBS.</p><p>The effectiveness of regular high frequency STN DBS was associated with a decrease in pathological low frequency oscillations and an increase in high frequency oscillations. These observations indicate that the effects of DBS are not only mediated by changes in firing rate, but also involve changes in neuronal firing patterns within the basal ganglia. The shift in neural oscillations from low to high frequency during effective STN DBS suggests that high frequency regular DBS suppresses pathological firing by entraining neurons to the stimulus pulses. </p><p>Therefore, results from this dissertation support the hypothesis that the underlying mechanism of effective DBS is its ability to entrain and regularize neuronal firing, therefore disrupting pathological patterns of activity within the basal ganglia.</p> / Dissertation