This study examined whether antidepressants delay the need for dopaminergic therapy or change the degree of motor impairment and disability in a population of early Parkinson's disease (PD) patients. Preclinical studies have indicated that antidepressants modulate signaling pathways involved in cell survival and plasticity, suggesting they may serve to both treat PD-associated depression and slow disease progression. A patient-level meta-analysis included 2064 patients from the treatment and placebo arms of the following trials: FS1, FS-TOO, ELLDOPA, QE2, TEMPO, and PRECEPT. Depression severity was determined at baseline, and antidepressant use was reported in a medication log each visit. Kaplan-Meier curves and time-dependent Cox proportional hazards models determined associations between depression severity and antidepressant use with the primary outcome, time to initiation of dopaminergic therapy. ANCOVAs determined associations with the secondary outcome, degree of motor impairment and disability, reported as annualized change in UPDRS scores from baseline to final visit. When controlling for baseline depression, the initiation of dopaminergic therapy was delayed for subjects taking tricyclic antidepressants compared with those not taking antidepressants. No significant differences were found in UPDRS scores for subjects taking antidepressants compared with those not taking antidepressants. Tricyclic antidepressants are associated with a delay in reaching the end point of need to start dopaminergic therapy. The lack of change in overall UPDRS scores suggests the delay was not attributable to symptomatic effects.
Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA) and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH-301, respectively. Similarly, dose- and time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.
In addition to alleviating depression, trophic responses produced by antidepressants may regulate neural plasticity in the diseased brain, which not only provides symptomatic benefit but also potentially slows the rate of disease progression in Parkinson's disease (PD). Recent in vitro and in vivo data provide evidence that neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. As such, we conducted a cross-sectional time-course study to determine whether antidepressant-mediated changes in neurotrophic factors occur in relevant brain regions in response to amitriptyline (AMI) treatment before and after intrastriatal 6-hydroxydopamine (6OHDA). Adult male Wistar rats were divided into seven cohorts and given daily injections (i.p.) of AMI (5mg/kg) or saline throughout the duration of the study. In parallel, various cohorts of intact or parkinsonian animals were sacrificed at specific time points to determine the impact of AMI treatment on trophic factor levels in the intact and degenerating nigrostriatal system. The left and right hemispheres of the substantia nigra, striatum, frontal cortex, piriform cortex, hippocampus, and anterior cingulate cortex were dissected, and BDNF and GDNF levels were measured with ELISA. Results show that chronic AMI treatment elicits effects in multiple brain regions and differentially regulates levels of BDNF and GDNF depending on the region. Additionally, AMI halts the progressive degeneration of dopamine (DA) neurons elicited by an intrastriatal 6-OHDA lesion. Taken together, these results suggest that AMI treatment elicits significant trophic changes important to DA neuron survival within both the intact and degenerating nigrostriatal system.
Neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult.
Multiple laboratories have recently demonstrated that long-term dopaminergic transplants form Lewy bodies in patients with Parkinson's disease. Debate has arisen as to whether these Lewy bodies form from the transfer of α synuclein from the host to the graft or whether they form from intrinsic responses of the graft from being placed into what was, or became, an inflammatory focus. To test whether the former hypothesis was possible, we grafted fetal rat ventral mesencephalon into the dopamine depleted striatum of rats that had previously received 6-hydroxydopamine lesions. One month after the transplant, rats received viral over expression of human α synuclein (AAV2/6-α synuclein) or green fluorescent protein (AAV2/6-GFP) into the striatum rostral to the grafts. Care was taken to make sure that the AAV injections were sufficiently distal to the graft so no cells would be directly transfected. All rats were sacrificed five weeks after the virus injections. Double label immunohistochemistry combined with confocal microscopy revealed that a small number of grafted tyrosine hydroxylase (TH) neurons (5.7% ± 1.5% (mean ± SEM) of grafted dopamine cells) expressed host derived α synuclein but none of the grafted cells expressed host-derived GFP. The α synuclein in a few of these cells was misfolded and failed to be digested with proteinase K. These data indicate that it is possible for host derived α synuclein to transfer to grafted neurons supporting the concept that this is one possible mechanism by which grafted dopamine neurons form Lewy bodies in Parkinson's disease patients.