Tricyclic Antidepressant Medications (TCAs) as a Disease-Modifying Therapy in Early Parkinson’s Disease.
Stimulated by the acknowledgement that a significant portion of PD patients experience depression (estimated 40-50%), and with evidence from animal models of depression indicating that anti-depressant medications increase levels of neurotrophic factors relevant to dopamine (DA) neuron function, we asked whether these medications had effects on the DA system relevant to parkinsonism. Our retrospective analysis of data from several clinical trials conducted by the Parkinson’s Study Group indicated that individuals with early PD with a history of use of tricyclic antidepressant drugs, and amitriptyline (AMI)(Elavil) in particular, exhibited a significant delay in the need for dopaminergic therapy (Paumier et al., 2012). In parallel animal model experiments we demonstrated that AMI treatment produced partial neuroprotection of nigrostriatal DA neurons following 6-hydroxydopamine insult, and that this result was associated with increased levels of the DA neurotrophic factor BDNF, in relevant brain regions (Paumier et al., 2015). Moving forward we incorporated nortriptyline (NOR)(Pamelor) into our studies as it represents the major metabolite of AMI that accumulates in brain and is a commonly prescribed tricyclic drug.
The prospect that antidepressant therapy, regardless of the presence of a depressive disorder, could benefit PD patients by slowing the rate of disease progression has been previously suggested, but never adequately explored. Therefore, it is important to determine whether antidepressant therapy provides additional therapeutic benefit for PD patients, thus providing a rationale for early intervention. Not only have antidepressants such as TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs) been shown to modulate important signaling pathways involved in cell survival and plasticity, but for the first time, we have in vitro and in vivo evidence that TCAs interact with and reduce the aggregation of alpha-synuclein (α-syn). These findings have important implications for the PD community as they suggest that TCA treatment can slow the rate of α-syn aggregation, reduce the accumulation of Lewy Body (LB) pathology and ultimately prevent or slow nigrostriatal degeneration in PD.
|AMI & NOR reduce accumulation of alpha-synuclein aggregates in a dose-related manner after injection of pre-formed fibrils in rats.|
Paumier KL, Sortwell CE, Madhavan L, Terpstra B, Daley BF, Collier TJ. (2015) “Tricyclic antidepressant treatment evokes regional changes in neurotrophic factors over time within the intact and degenerating nigrostriatal system.” Exp Neurol. 266:11-21. PMID: 25681575
Paumier KL, Sortwell CE, Madhavan L, Terpstra B, Celano SL, Green JJ, Imus NM, Marckini N, Daley B, Steece-Collier K, Collier TJ. (2015) “Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of parkinsonism.” Neuropsychopharmacology. 40(4):874-83. PMID: 25267343
Paumier KL, Siderowf AD, Auinger P, Oakes D, Madhavan L, Espay AJ, Revilla FJ, Collier TJ; Parkinson Study Group Genetics Epidemiology Working Group. (2012) “Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson's disease.” Mov Disord. 27(7):880-7. PMID: 22555881
Mechanisms of Aging as they Contribute to Neurodegenerative Diseases and Response to Therapy.
Aging is acknowledged to be the greatest risk factor for development of Parkinson’s disease (PD). Yet, early studies highlighted distinctions between the two, yielding the dogma that cellular mechanisms associated with aging of midbrain dopamine (DA) neurons and those related to DA neuron degeneration in PD are distinct and unrelated. We have revisited this issue, incorporating accumulated knowledge concerning the likely participants in degeneration associated with PD and current anatomical techniques, in tissue from aging nonhuman primates. In addition, we have exploited the acknowledged regional differences in midbrain DA neuron vulnerability to degeneration in PD to test the hypothesis that to the extent that aging and degeneration of DA neurons in PD are linked by cellular mechanisms, markers of acknowledged cellular risk factors will accumulate with advancing age in a region-specific pattern that mimics the pattern of degeneration observed in PD. Based on histochemical evidence for markers of alpha-synuclein, the ubiquitin/proteasome system, lysosome system, oxidative/nitrative stress, and glia we conclude that aging is linked to PD at the level of cellular mechanisms and actively produces a vulnerable pre-parkinsonian state. We go on to propose a “Stochastic Acceleration Hypothesis” of PD in which the common cellular mechanisms of DA neuron demise present in aging and PD are accelerated in PD by a combination of genetic and environmental factors that are distinct, yielding each patients’ version of the disease.
Collier TJ, Kanaan NM, Kordower JH. (2011) “Ageing as a primary risk factor for Parkinson’s disease: evidence from studies of non-human primates.” Nat Rev Neurosci. 12:359-66. PMID 21587290.
Kanaan NM, Kordower JH, Collier TJ. (2008) “Age-related changes in dopamine transporters and accumulation of 3-nitrotyrosine in rhesus monkey midbrain dopamine neurons: relevance to selective neuronal vulnerability in degeneration.”
Eur J Neurosci. 27:3205-15. PMID 18598263.
Kanaan NM, Kordower JH, Collier TJ. (2007) “Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamine neurons: relevance to selective neuronal vulnerability.” J Comp Neurol. 502:683-700. PMID 17436290.
In addition, we continue to incorporate aging as a variable in our studies of responses to experimental therapeutics. Using cell transplantation as a tool for assessing the environment of the aging brain, we previously have shown that implanted cells survive more poorly in the aged brain and provide diminished reinnervation (Collier et al., 1999). In a recent study we show that even when adequate numbers of transplanted DA neurons survive, these cells make fewer contacts with neurons in the host brain and show delayed or absent recovery of behavioral abnormalities (Collier et al., 2015).
Collier TJ, Sortwell CE, Daley BF. (1999) “Diminished viability, growth, and behavioral efficacy of fetal dopamine neuron grafts in aging rats with long-term dopamine depletion: an argument for neurotrophic supplementation.” J Neurosci. 19(13):5563-73. PMID: 10377363
Collier TJ, O'Malley J, Rademacher DJ, Stancati JA, Sisson KA, Sortwell CE, Paumier KL, Gebremedhin KG, Steece-Collier K. (2015) “Interrogating the aged striatum: Robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration. Neurobiol Dis. 77:191-203. PMID: 25771169
Neural Progenitor Cells for Neuroprotection in a Rat Model of Parkinson’s Disease.
Stem cell research offers enormous potential for treating many diseases of the nervous system. At present, therapeutic strategies in stem cell research segregate into two approaches: cell transplantation or endogenous cell stimulation. Realistically, future cell therapies most likely will involve a combination of these two approaches, a theme of our current research. Our recent findings indicate that there exists a ‘synergy’ between exogenous (transplanted) and endogenous stem cell actions that can be utilized to achieve therapeutic ends. We have found that transplanting undifferentiated neural progenitor cells into the striatum and midbrain of the nigrostriatal DA system damaged in a rat model of Parkinson’s disease reduces the death of DA neurons by approximately 50%. Unexpectedly, transplantation of these progenitor cells stimulates proliferation of endogenous progenitor cells in the host brain and migration of these cells to the site of transplanted cells. Inhibition of this response of host progenitor cells blunts the neuroprotective effects of the transplanted progenitor cells, suggesting that the two cell populations collaborate to produce therapeutic effects. Using RNA-silencing techniques we find that inhibition of the protein sonic hedgehog (SHH) expressed my transplanted progenitor cells diminishes both stimulation of host progenitor cells and neuroprotection of the DA system.
Madhavan L, Daley BF, Sortwell CE, Collier TJ. (2012) “Endogenous neural precursors influence grafted neural stem cells and contribute to neuroprotection in the parkinsonian rat.” Eur J Neurosci. 35(6):883-95. PMID: 22417168
Madhavan L, Collier TJ (2010) “A synergistic approach for neural repair: cell transplantation and induction of endogenous precursor cell activity.” Neuropharmacol. 58:835-44. PMID 19853620.
Madhavan L, Daley BF, Paumier K, Collier TJ (2009) “Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson’s disease.” J Comp Neurol. 515:102-15. PMID 19399899.
Collier Laboratory Personnel
|Pictured Left to Right: Tim Collier and Brian Daley.|
|Pictured Left to Right: Tim Collier, Nastassja Imus, Nathan Marckini (back row), Brian Daley, Ivette Sandoval|
Brian graduated from S.U.N.Y. Brockport in 1985 with a degree in Biotechnology. That same year he began working with Tim at the University of Rochester in upstate New York. Since then they have worked together at Rush University Medical Center in Chicago, the University of Cincinnati in Cincinnati Ohio, and now at Michigan State University in Grand Rapids Michigan. His areas of expertise include all aspects of small animal stereotaxic surgery and histological preparation and analysis of brain tissue. He is a resource for technical information accumulated over his 30 years as a research associate.
Ivette Sandoval, Ph.D.
Research Assistant Professor
Ivette graduated from Baylor College of Medicine in 2012 with a degree in Biochemistry & Molecular Biology. During her graduate training Ivette created and characterized a mouse model for detection of gene correction events and mechanisms of DNA repair in retinal rod photoreceptor cells. She also characterized the efficiency of in vivo genome editing in photoreceptor cells using zinc finger nucleases (ZFNs) and recombinant adeno-associated viral vector (rAAV) technologies as a potential therapy for retinal degeneration.Back to Top
Caryl Sortwell, Ph.D., Research Center for Brain Repair, Rush-Presbyterian Medical Center, 1996-1998. Professor, Michigan State University, Dept. Translational Science & Molecular Medicine, Grand Rapids, MI.
Mark Pitzer, Ph.D., Research Center for Brain Repair, Rush-Presbyterian Medical Center, 1998-2001. Associate Professor, Dept. Psychology, University of Portland, Portland, OR.
Susan McGuire, Ph.D., Research Center for Brain Repair, Rush-Presbyterian Medical Center, 2000-2002. Associate Professor, Loyola University Medical School, Chicago, IL
Lalitha Madhavan, Ph.D., Department of Neurology, University of Cincinnati,
2006-2010. Assistant Professor, University of Arizona, Tucson, AZ.
Patrick Martin, M.D./Ph.D. program, Department of Neurobiology and Anatomy, University of Rochester School of Medicine, Terminal M.S.
Deanna Marchionini, Ph.D. program, Neuroscience, Rush University, 2000-2005. Post-Doctoral training Dept. Neurology, Columbia University, New York, NY. Director, Early Discovery Initiative, CHDI Foundation, New York, NY.
Nick Kanaan, Ph.D. program, Neuroscience, Rush University, 2001-2007. Postdoctoral training, Northwestern University, Chicago, IL. Assistant Professor, Michigan State University, Dept. Translational Science & Molecular Medicine, Grand Rapids, MI.
Katrina Paumier, Ph.D. program, Neuroscience, University of Cincinnati, 2004-2010. Postdoctoral training, Pfizer, Groton, CT. Senior Scientist, DIAN Cliical Trials Unit, Washington University, St. Louis, MO.