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«BY NEUROTROPHIC FACTORS IN NONHUMAN PRIMATES WITH DOPAMINE DEPLETION by Krishna Subramanian Bachelor of Technology, Biotech., Anna University, 2007 ...»

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RESTORATION OF MOTOR AND NON-MOTOR FUNCTIONS BY NEUROTROPHIC

FACTORS IN NONHUMAN PRIMATES WITH DOPAMINE DEPLETION

by

Krishna Subramanian

Bachelor of Technology, Biotech., Anna University, 2007

Submitted to the Graduate Faculty of

Medicine in partial fulfillment

of the requirements for the degree of

Doctor of Philosophy

University of Pittsburgh

2013

UNIVERSITY OF PITTSBURGH

SCHOOL OF MEDICINE

This dissertation was presented by Krishna Subramanian It was defended on August 22, 2013 and approved by Barry J. Hoffer, MD, PhD, Department of Neurosurgery, Case Western Reserve University, Case School of Medicine Brian M. Davis, PhD, Department of Neurobiology Susan R. Sesack, PhD, Department of Neuroscience Alan F. Sved, PhD, Department of Neuroscience Michael J. Zigmond, PhD, Department of Neurology Dissertation Advisor: Judy L. Cameron, PhD, Department of Psychiatry ii iii

RESTORATION OF MOTOR AND NON-MOTOR FUNCTIONS BY

NEUROTROPHIC FACTORS IN NONHUMAN PRIMATES WITH DOPAMINE

DEPLETION

Krishna Subramanian University of Pittsburgh, 2013 Parkinson’s disease (PD) is a progressive debilitating neurodegenerative disorder characterized by resting tremor, rigidity, bradykinesia and postural instability. As the disease progresses there is a loss of dopamine (DA) neurons in the substantia nigra projecting to the various forebrain and sub-cortical regions. Current treatments for PD are unable to prevent or curtail the neurodegenerative process; so rescuing remaining dopamine in the mid-brain has been the recent focus of research examining the effectiveness of neurotrophic factors (NTFs) in the treatment of PD. In this dissertation, the ability of three novel, recently discovered NTFs to restore DA neurons and motor function in a nonhuman primate model of PD was examined. The NTFs were Cerebral Dopamine Neurotrophic Factor (CDNF) and two variants of Neurturin (NRTN), N2 and N4, that have mutations that prevent binding to heparin sulfate binding sites in the brain. These studies used the unilateral low dose (0.15 ± 0.001 mg/kg) monkey 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) model of PD to cause loss of DA neurons. Six groups of monkeys were studied: vehicle-treated (negative control), Glial Cell-line Derived Neurotropic Factor (GDNF, positive control), two groups of CDNF-treated monkeys(450 µg and 150 µg), and N2 and N4-treated groups. After MPTP, monkeys developed moderate symptoms of PD (PD rating scale score=7.9±0.5 on a scale of 0-22, p0.001), motor dysfunction and increased daytime sleepiness. After three months of infusions, all three NTFs (150 µg CDNF, N2 and N4) significantly increased the number of DA neurons in the substantia nigra, p=0.03, and improved parkinsonian symptoms measured by rating scale, p0.001. Most motor functions were

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improved daytime sleep duration, bouts and wake-latency (p=0.02, p=0.06 and p=0.02, respectively). In summary, CDNF, N2 and N4 trophic factors are neurorestorative to DA neurons, motor function is tightly correlated with DA neuronal number, and N4 improved the non-motor symptom of increased daytime sleepiness in this monkey PD model. These factors hold promise for clinical therapy for PD patients.

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ABBREVIATIONS

1.0 GENERAL INTRODUCTION

1.1 PARKINSON’S DISEASE (PD): OVERVIEW

1.1.1 Clinical Characteristics of PD

1.1.2 Etiology of PD

1.2 THE BASAL GANGLIA

1.2.1 Anatomy of basal ganglia circuits

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1.2.2 Physiology of the basal ganglia

1.3 SYMPTOMS IN PD

1.3.1 Motor symptoms in PD

1.3.2 Non-motor symptoms in PD

1.4 ANIMAL MODELS OF PD

1.4.1 The 6-OHDA model of PD

1.4.2 MPTP model of PD

1.4.3 Biochemical changes in PD

1.5 NEUROTROPHIC FACTORS THAT SUPPORT DA NEURONS

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1.5.2 Neurturin, NRTN

1.5.3 Cerebral Dopamine Neurotrophic Factor, CDNF

1.6 SPECIFIC AIMS

1.6.1 Specific Aim 1

1.6.2 Specific Aim 2

1.6.3 Specific Aim 3

2.0 EFFECTS OF CDNF, N2 AND N4 ON RECOVERY OF MOTOR FUNCTION IN

MPTP-TREATED MONKEYS

2.1 INTRODUCTION

2.2 MATERIALS AND METHODS

2.2.1 Animals

2.2.2 MPTP Administration

2.2.3 Experimental design

2.2.4 Statistical Analysis

2.3 RESULTS

2.3.1 Effect of MPTP Administration on Motor Movement

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2.3.3 Post-mortem cell count data and prediction of post-infusions motor measures based on cell counts measures

2.4 DISCUSSION

2.4.1 Effects of unilateral low-dose MPTP on motor movement

–  –  –

3.1 INTRODUCTION

3.2 MATERIALS AND METHODS

3.2.1 Animals

3.2.2 MPTP Administration

3.2.3 Experimental design

3.2.4 Sleep Assessments





3.2.5 Assessment of Motor Function

3.2.6 Statistical Analysis

3.3 RESULTS

3.4 DISCUSSION

4.0 EFFECTS OF GDNF, CDNF, N2 AND N4 ON DAYTIME SLEEP IN MPTPTREATED MONKEYS

4.1 INTRODUCTION

4.2 MATERIALS AND METHODS

4.2.1 Animals

4.2.2 MPTP Administration

4.2.3 Experimental design

4.2.4 Sleep function assessments

4.2.5 Assessment of Motor Function

4.2.6 Statistical Analysis

4.3 RESULTS

4.4 DISCUSSION

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5.1 DISTRIBUTION OF NTFS IN BRAIN TISSUE

5.2 DELIVERY OF NTF’S TO THE BRAIN

5.3 OPTIMAL NTF DOSE AND DOSING REGIMEN

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THERAPIES

5.5 THE EFFECTIVENESS OF TREATING NON-MOTOR SYMPTOMS OF PD

WITH NTF’S

5.6 FINAL CONCLUSIONS

APPENDIX A

BIBLIOGRAPHY

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Figure 1. Basic circuit diagram of basal ganglia…………………………………….

.10 Figure 2. MRI of monkey brain after administration of NTF.……………………... 65 Figure 3. Experimental design.

……………………………………………………….. 65 Figure 4. Activity measured before and after MPTP……………………………….. 69 Figure 5. Movement measured before and after MPTP……………………………..70 Figure 6. Balk rate during mMAP testing.……………………………………………71 Figure 7. Changes in motor behavior by homepen assessments……………………..72 Figure 8. Changes in Parkinson’s rating scale from Post-MPTP to Post-Infusions..77 Figure 9. Changes to the total motion scored in homepen…………………………...78 Figure 10. Number of dopamine neurons post-infusions……………………………79 Figure 11. Correlation of rating scale, fine motor behavior and DA cell counts…...81 Figure 12. Correlation between DA cell counts and movement behavior…………..82 Figure 13. Correlation between DA cell counts and homepen behavior……………83 Figure 14. Comparison of the population in post-mortem analysis…………………83 Figure 15. The receiver-operator characteristic (ROC) curves for sleep criteria…98 Figure 16. Changes to sleep behavior after MPTP…………………………………...99 Figure 17. Correlation between sleep behavior and Parkinson’s rating scale……100 Figure 18. Changes to sleep behavior after NTF treatment………………………..116 Figure 19. Correlation between, cell counts and latency to wake in the morning...117

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6-OHDA – 6-hydroxydopamine AAV – recombinant Adeno-associated virus BDNF – Brain-derived neurotrophic factor CDNF – Cerebral dopamine neurotrophic factor CNS – Central nervous system CPAP – continuous positive air pressure CSF – Cerebrospinal fluid DA – Dopamine DAT – Dopamine transporter DMNC – dorsal motor nuclear complex of IX and X DOPAC – dihydroxyphenylacetic acid EMG – Electromyography GABA – γ-aminobutyric acid GDNF – Glial cell-line derived neurotrophic factor GFL – GDNF family of ligands GHRH – Growth hormone releasing hormone GI -- Gastrointestinal GPe – Globus pallidus, external segment GPi – Globus pallidus, internal segment HVA – Homovanillic acid

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IRP – Iron-regulatory element-binding proteins IV – Intravenous LB – Lewy body M1 – Primary motor cortex MANF – Mesencephalic astrocyte-derived neurotrophic factor MAO – Monoamine oxidase MFB – Medial forebrain bundle MPDP – 1-methyl-4-phenyl-2,3-dihydropyridinium MPP – 1-methyl-4-phenyl-pyridinium ion MPPP – 1-methyl-4-phenyl-4-propionoxy-piperidine MPTP – 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MSN – Medium spiny neurons NGF – Nerve growth factor NRTN – Neurturin NTF – Neurotrophic factor OCD – Obsessive-compulsive disorder PD – Parkinson’s disease REM – Rapid eye movement ROS – Reactive oxygen species S1 – Primary sensory cortex SC – Subcutaneous SMA – Supplementary motor area

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SNpr – Substantia nigra, pars reticulata STN – Subthalamic nucleus TAN – Tonically active neurons UPDRS – Unified Parkinson’s disease rating scale VMAT – Vesicular monoamine transporter VTA – Ventral tegmental area

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1.1.1 Clinical Characteristics of PD James Parkinson in 1817 wrote “An essay on the shaking palsy” and was the first person to describe in detail the clinical symptoms of this disease that later went on to bear his name [Parkinson, 1817]. Jean-Martin Charcot, a famous neurologist at la Salpêtrière hospital in Paris who contributed significantly to our understanding of this disease through his lectures sixty years later, referred to as Charcot’s lectures, distinguished this disease from other tremor-related neurological disorders and gave further details about the manifestation and time course of the progression of the disease as it was understood in the late 19th century (called ‘paralysis agitans’) [Charcot, 1877]. Charcot gave credit to Parkinson for his pioneering descriptions by referring to this disease as “maladie de Parkinson” or Parkinson’s disease (PD), as it is now called [Charcot, 1877]. However, PD existed long before James Parkinson described six such cases in detail in

1817. Galen of Pergamon observed a similar disease and wrote an Egyptian papyrus (1350-1200 BC) that described it, suggesting that parkinsonism was occurring at that time [Forno, 1996].

Similarly, characteristics of the disease were also described in Charaka Samhita (400 – 600 BC) [Prasad et al., 2004; Nishteswar, 2011], one of the two foundational textbooks of Ayurveda. A

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disease was called “kampa vata” [Nishteswar, 2011]. Leonard da Vinci also described many characteristics of the disease between 1489 and 1506 AD [Forno, 1996].

The cardinal features of PD are the movement problems of rigidity, resting tremor, and bradykinesia (i.e., abnormal slowness of movement). In later stages of the disease, loss of postural reflexes leads to postural instability and postural deformities associated with rigidity, such as flexed posture of the neck, trunk, elbows and knees are present [Hughes et al., 1992, 1993; Jankovic, 2008]. Patients with PD also exhibit a variety of secondary motor symptoms that affect their functioning such as freezing of gait, blank facial expression and speech disorders [Lang et al., 1998].

Non-motor features of the disease are common and are often considered the most debilitating limitations to normal daily functioning of patients [McDowell et al., 2012;

Videnovic et al., 2012]. Roughly 90% of patients have substantial impact on their quality of life because of these non-motor symptoms, yet they are under-recognized because they are not considered part of the cardinal clinical features required for diagnosis of this disease [Chaudhuri et al., 2010]. These non-motor symptoms include sleep disturbances, anosmia, autonomic dysfunction, decreased motivation, depression, anxiety and cognitive dysfunction [Chaudhuri et al., 2010]. Interestingly, James Parkinson described the presence of sleep disturbances and other non-motor symptoms in his original essay [Parkinson, 1817].

PD is a progressive neurodegenerative disease of the nervous system [Lang et al., 1998;

Jankovic, 2008]. There are no biomarkers that are currently recognized for the early ante-mortem diagnosis of PD. The motor system manifestations of the disease are only evident after the pathology of the disease has reached an advanced stage, with typically over 60-80% of the

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appear [Bernheimer et al., 1973; Hornykiewicz, 1998; Jankovic, 2008]. At this time, the diagnosis of the disease still relies upon the presence, severity, progression of clinical motor symptoms of the disease and confirmation of diagnosis depends on post-mortem neuropathology [Hughes et al., 1992, 1993; Litvan et al., 2003; Braak et al., 2003, 2004; Jankovic, 2008]. It is currently recognized that development of specific biomarkers for PD, allowing for earlier suspicion of the disease, would be useful to identify groups at risk of developing PD and would provide patients with an opportunity to start a neurorestorative therapy early in the disease [Airavaara et al., 2011; Aron et al., 2011].



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