TY - JOUR
T1 - Evaluation of microglia in a rodent model of Parkinson's disease primed with L-DOPA after sub-anesthetic ketamine treatment
AU - Pottenger, Ayumi E.
AU - Bartlett, Mitchell J.
AU - Sherman, Scott J.
AU - Falk, Torsten
AU - Morrison, Helena W.
N1 - Funding Information:
Imaging experiments were conducted at UArizona Imaging Cores Marley and Life Science North, supported by the Arizona Technology and Research Initiative Fund, A.R.S.§15-1648. Research support: Arizona Biomedical Research Commission [ ADHS18-198846 , SJS, TF] and National Institute of Health [ R56-NS109608 , TF].
Funding Information:
Imaging experiments were conducted at UArizona Imaging Cores Marley and Life Science North, supported by the Arizona Technology and Research Initiative Fund, A.R.S.?15-1648. Research support: Arizona Biomedical Research Commission [ADHS18-198846, SJS, TF] and National Institute of Health [R56-NS109608, TF].
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/11/20
Y1 - 2021/11/20
N2 - Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characterized by motor dysfunction. While PD symptoms are well treated with L-DOPA, continuous use can cause L-DOPA-induced dyskinesia (LID). We have previously demonstrated that sub-anesthetic ketamine attenuated LID development in rodents, measured by abnormal involuntary movements (AIMs), and reduced the density of maladaptive striatal dendritic mushroom spines. Microglia may play a role by phagocytosing maladaptive neuronal spines. In this exploratory study, we hypothesized that ketamine would prevent AIMs and change microglia ramified morphology – an indicator of a microglia response. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats were primed with daily injections of L-DOPA for 14 days, treated on days 0 and 7 for 10-hours with sub-anesthetic ketamine (i.p.), and we replicated that this attenuated LID development. We further extended our prior work by showing that while ketamine treatment did lead to an increase of striatal interleukin-6 in dyskinetic rats, indicating a modulation of an inflammatory response, it did not change microglia number or morphology in the dyskinetic striatum. Yet an increase of CD68 in the SNpc of 6-OHDA-lesioned hemispheres post-ketamine indicates increased microglia phagocytosis suggestive of a lingering microglial response to 6-OHDA injury in the SNpc pointing to possible anti-inflammatory action in the PD model in addition to anti-dyskinetic action. In conclusion, we provide further support for sub-anesthetic ketamine treatment of LID. The mechanisms of action for ketamine, specifically related to inflammation and microglia phagocytic functions, are emerging, and require further examination.
AB - Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characterized by motor dysfunction. While PD symptoms are well treated with L-DOPA, continuous use can cause L-DOPA-induced dyskinesia (LID). We have previously demonstrated that sub-anesthetic ketamine attenuated LID development in rodents, measured by abnormal involuntary movements (AIMs), and reduced the density of maladaptive striatal dendritic mushroom spines. Microglia may play a role by phagocytosing maladaptive neuronal spines. In this exploratory study, we hypothesized that ketamine would prevent AIMs and change microglia ramified morphology – an indicator of a microglia response. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats were primed with daily injections of L-DOPA for 14 days, treated on days 0 and 7 for 10-hours with sub-anesthetic ketamine (i.p.), and we replicated that this attenuated LID development. We further extended our prior work by showing that while ketamine treatment did lead to an increase of striatal interleukin-6 in dyskinetic rats, indicating a modulation of an inflammatory response, it did not change microglia number or morphology in the dyskinetic striatum. Yet an increase of CD68 in the SNpc of 6-OHDA-lesioned hemispheres post-ketamine indicates increased microglia phagocytosis suggestive of a lingering microglial response to 6-OHDA injury in the SNpc pointing to possible anti-inflammatory action in the PD model in addition to anti-dyskinetic action. In conclusion, we provide further support for sub-anesthetic ketamine treatment of LID. The mechanisms of action for ketamine, specifically related to inflammation and microglia phagocytic functions, are emerging, and require further examination.
KW - Basal ganglia
KW - Dendritic spines
KW - Inflammation
KW - Interleukin-6
KW - Levodopa
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UR - http://www.scopus.com/inward/citedby.url?scp=85115643983&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2021.136251
DO - 10.1016/j.neulet.2021.136251
M3 - Article
C2 - 34536508
AN - SCOPUS:85115643983
SN - 0304-3940
VL - 765
JO - Neuroscience Letters
JF - Neuroscience Letters
M1 - 136251
ER -