Chronic Amitriptyline Treatment Attenuates Nigrostriatal Degeneration and Significantly Alters Trophic Support in a Rat Model of Parkinsonism

Abstract

In addition to alleviating depression, long-term adaptive changes induced by antidepressants may regulate neural plasticity in the diseased brain, providing symptomatic and disease-modifying effects in Parkinson's disease. The present study investigated whether chronic treatment with a frequently prescribed tricyclic antidepressant was neuroprotective in a 6-hydroxydopamine (6-OHDA) rat model of parkinsonism. In lesioned animals, chronic amitriptyline (AMI; 5 mg/kg) treatment resulted in a significant sparing of tyrosine hydroxylaseimmunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) compared with saline treatment. Additionally, striatal fibers were preserved and functional motor deficits were attenuated. Although 6-OHDA lesions did not induce anhedonia in our model, the dose of AMI utilized had antidepressant activity as demonstrated by reduced immobility. Recent in vitro and in vivo data provide evidence that trophic 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. Therefore, we investigated whether AMI mediates changes in these specific trophic factors in the intact and degenerating nigrostriatal system. Chronic AMI treatment mediates an increase in nigral BDNF both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. However, over time, AMI reduced BDNF levels in the striatum, indicating tricyclic therapy differentially regulates trophic factors within the nigrostriatal system. Combined, these results suggest that AMI treatment attenuates dopamine neuron loss and elicits significant trophic changes relevant to dopamine neuron survival.

Imipramine and amitriptyline ameliorate the rotenone model of Parkinson’s disease in rats

“…Herein, treatment with AMI and IMI attenuated the rotenone-induced dopaminergic neuronal loss in SN along with restoration in the striatal DA level; effects ϭϳ supported by a previous finding that TCA delayed the need for initiating dopaminergic therapy in PD patients (Paumier et al, 2012). Moreover, AMI prevented the degeneration of nigrostriatal dopaminergic neurons as well as the motor deficits in the 6-hydroxydopamine rat model of PD (Paumier et al, 2015). Similarly, an enhancement in rats' motor performance and coordination in the open field and rotarod tests, respectively, was evident herein following treatment with both drugs.…”

“…In the present study, AMI and IMI were daily administered for 35 consecutive days beginning 2 weeks prior to rotenone administration to account for the delay in the therapeutic efficacy of antidepressants (Malberg and Blendy, 2005;Martinez-Turrillas et al, 2005;Paumier et al, 2015). On the 15 th day from the start of the experiment, rats in appropriate groups received rotenone or its solvent DMSO every other day for 3 weeks for a total of 11 injections (Fig 1).…”

“…Animals of groups III & IV received daily AMI (5 mg/kg, i.p.) (Paumier et al, 2015) and IMI (10 mg/kg, i.p.) (Daniel et al, 1981) for 35 consecutive days dissolved in physiological saline, respectively.…”

“…Thereafter, an experimental study using 6-hydroxydopamine rat model of PD verified that AMI attenuates motor deficits and preserves dopaminergic neurons in substantia nigra (SN) (Paumier et al, 2015).…”

“…Increased trophic support elicited by AMI within the nigrostriatal system is a likely contributor to the dopaminergic neuron protection; however, the pattern and magnitude of such action suggest that additional mechanisms are involved (Paumier et al, 2015).…”