TY - JOUR
T1 - Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous L-DOPA delivery in the 6-OHDA model of Parkinson's disease
AU - Mulas, Giovanna
AU - Espa, Elena
AU - Fenu, Sandro
AU - Spiga, Saturnino
AU - Cossu, Giovanni
AU - Pillai, Elisabetta
AU - Carboni, Ezio
AU - Simbula, Gabriella
AU - Jadžić, Dragana
AU - Angius, Fabrizio
AU - Spolittu, Stefano
AU - Batetta, Barbara
AU - Lecca, Daniela
AU - Giuffrida, Andrea
AU - Carta, Anna R.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Neuroinflammation is associated with L-DOPA treatment in Parkinson's disease (PD), suggesting a role in L-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of L-DOPA treatment. Diversely from oral L-DOPA, continuous intrajejunal L-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) L-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. L-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24 h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any L-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic L-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.
AB - Neuroinflammation is associated with L-DOPA treatment in Parkinson's disease (PD), suggesting a role in L-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of L-DOPA treatment. Diversely from oral L-DOPA, continuous intrajejunal L-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) L-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. L-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24 h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any L-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic L-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.
KW - Cytokine
KW - Dyskinesia
KW - Inflammation
KW - L-DOPA
KW - Microglia
KW - Parkinson
KW - TNF-alpha
UR - http://www.scopus.com/inward/record.url?scp=84990249384&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990249384&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2016.09.013
DO - 10.1016/j.expneurol.2016.09.013
M3 - Article
C2 - 27697481
AN - SCOPUS:84990249384
VL - 286
SP - 83
EP - 92
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
ER -