Nitrosative and cognitive effects of chronic l-DOPA administration in rats with intra-nigral 6-OHDA lesion

Ramirez-García, Gabriel; Palafox-Sánchez, Victoria; Limón, Ilhuicamina Daniel

doi:10.1016/j.neuroscience.2015.01.047

Cited by 21 publications

(14 citation statements)

References 89 publications

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“…However, while we observed an increase in GFAP immunoreactivity, reflecting astrogliosis, within the ipsilateral lesioned striatum, there were no group-wise differences between vehicle and L-DOPA treated rats, nor any correlation between GFAP signal and either AIMs or striatal volume change, arguing against a major contribution of astrogliosis to the volume expansion noted here. These data are at odds with some previous studies which, like ours, showed elevated GFAP in the lesioned striatum but, in contrast, showed a further elevation after L-DOPA treatment (Bortolanza et al, 2015;Ramírez-García et al, 2015). These discrepancies may reflect the alternative route or higher doses of L-DOPA administered in these previous studies (30 and 100 mg/kg orally, respectively) when compared to 6.25 mg/kg s.c. used here.…”

Section: Discussioncontrasting

confidence: 99%

Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

et al. 2020

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Dyskinesia associated with chronic levodopa treatment in Parkinson's disease is associated with maladaptive striatal plasticity. The objective of this study was to examine whether macroscale structural changes, as captured by magnetic resonance imaging (MRI) accompany this plasticity and to identify plausible cellular contributors in a rodent model of levodopa-induced dyskinesia. Adult male Sprague-Dawley rats were rendered hemi-parkinsonian by stereotaxic injection of 6-hydroxydopamine into the left medial forebrain bundle prior to chronic treatment with saline (control) or levodopa to induce abnormal involuntary movements (AIMs), reflective of dyskinesia. Perfusion-fixed brains underwent ex vivo structural MRI before sectioning and staining for cellular markers. Chronic treatment with levodopa induced significant AIMs (p < 0.0001 versus saline). The absolute volume of the ipsilateral, lesioned striatum was increased in levodopatreated rats resulting in a significant difference in percentage volume change when compared to saline-treated rats (p < 0.01). Moreover, a significant positive correlation was found between this volume change and AIMs scores for individual levodopatreated rats (r = 0.96; p < 0.01). The density of Iba1+ cells was increased within the lesioned versus intact striatum (p < 0.01) with no difference between treatment groups. Conversely, Iba1+ microglia soma size was significantly increased (p < 0.01) in the lesioned striatum of levodopa-treated but not saline-treated rats. Soma size was not, however, significantly correlated with either AIMs or MRI volume change. Although GFAP+ astrocytes were elevated in the lesioned versus intact striatum (p < 0.001), there was no difference between treatment groups. No statistically significant effects of either lesion or treatment on RECA1, a marker for blood vessels, were observed. Collectively, these data suggest chronic levodopa treatment in 6-hydroxydopamine lesioned rats is

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Section: Discussioncontrasting

confidence: 99%

Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

et al. 2020

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“…Junior et al, 2020). Notably, the L-DOPA dyskinesiogenic treatment was reported to cause a robust activation of glial cells in the striatum of hemiparkinsonian rats (Bortolanza et al, 2015a;Ramirez-Garcia et al, 2015;Del-Bel et al, 2016;Mulas et al, 2016;Carta et al, 2017). Present observations in our dyskinetic hemiparkinsonian mouse model corroborate these data and confirm the presence of activated astrocytes and microglia in the dorsal part of the striatum depleted in dopaminergic nerve fibers.…”

Section: Lid Occurrence In Partially Lesioned Hemiparkinsonian Micesupporting

confidence: 88%

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

et al. 2021

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Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-α levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-α secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-α release in glutamate-activated astrocytes. TNF-α, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-α by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism.

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“…In rodents, using 6‐OHDA‐lesion plus chronic l ‐DOPA treatment, Bortolanza, Cavalcanti‐Kiwiatkoski, et al (2015) and Ramírez‐García et al () showed a dramatic regulation of astrocytosis in the striatum, supporting the hypothesis of a pivotal role in l ‐DOPA‐induced secondary effects such as dyskinesia (Figure ). There was an enlargement of astrocyte cell bodies, a remodeling of processes and an increase in astrocyte number that indicate reactive gliosis (see Bortolanza, Cavalcanti‐Kiwiatkoski, et al, 2015 for detailed description).…”

Section: Are Astrocytes a Key Element In The L‐dopa‐induced Dyskinesia?mentioning

confidence: 82%

“…These cells may be involved in the coordinated activity networks that are fundamental in motor control (Cui et al, ). Therefore, astrocytes may participate in striatum dysfunction in brain disorders since imbalances in the activities of pathways underlie motor deficits in PD (Bortolanza, Cavalcanti‐Kiwiatkoski, et al, 2015; Charron et al, ; Kravitz et al, ; Ramírez‐García, Palafox‐Sánchez, & Limón, ).…”

Section: Astrocytes Are Active Partners Of Neuronsmentioning

confidence: 99%

l-DOPA-induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements?

Del‐Bel

Bortolanza

Pereira

et al. 2016

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Inflammation in Parkinson's disease (PD) is a new concept that has gained ground due to the potential of mitigating dopaminergic neuron death by decreasing inflammation. The solution to this question is likely to be complex. We propose here that the significance of inflammation in PD may go beyond the nigral cell death. The pathological process that underlies PD requires years to reach its full extent. A growing body of evidence has been accumulated on the presence of multiple inflammatory signs in the brain of PD patients even in very late stages of the disease. Because neuron-microglia-astrocyte interactions play a major role in the plasticity of neuronal response to l-DOPA in post-synaptic neurons, we focused this review on our recent results of l-DOPA-induced dyskinesia in rodents correlating it to significant findings regarding glial cells and neuroinflammation. We showed that in the rat model of PD/l-DOPA-induced dyskinesia there was an increased expression of inflammatory markers, such as the enzymes COX2 in neurons and iNOS in glial cells, in the dopamine-denervated striatum. The gliosis commonly seem in PD was associated with modifications in astrocytes and microglia that occur after chronic treatment with l-DOPA. Either as a cause, consequence, or promoter of progression of neuronal degeneration, inflammation plays a role in PD. The key aims of current PD research ought to be to elucidate (a) the time sequence in which the inflammatory factors act in PD patient brain and (b) the mechanisms by which neuroinflammatory response contributes to the collateral effects of l-DOPA treatment.

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Nitrosative and cognitive effects of chronic l-DOPA administration in rats with intra-nigral 6-OHDA lesion

Cited by 21 publications

References 89 publications

Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

l-DOPA-induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements?

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