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

Abstract

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.

Striatal spreading depolarization: Possible implication in levodopa‐induced dyskinetic‐like behavior

“…In fact, during PD, inflammatory features have been found to be coupled with changes in astrocytes and microglia after long‐term l ‐dopa treatment. Thus, inflammation and abnormal glial function may play a crucial role in PD and LID induction progression . Similarly, it has been reported that glial activity is of critical importance during SD.…”

Repurposing an established drug: an emerging role for methylene blue in L‐DOPA‐induced dyskinesia

“…We cannot exclude that MB is acting throughout another mechanism besides inhibition of sGC or NOS. Non‐neuronal mechanisms, as neuroinflammation, were recently proposed to influence LID (Bortolanza et al ., ,b; Del‐Bel et al ., ; Mulas et al ., ; Carta et al ., ). MB is able to inhibit prostacyclin synthesis (Martin et al ., ) and to suppress pro‐inflammatory cytokines and microglial activation (Dibaj et al ., ; Fenn et al ., ; Xu et al ., ), which have been directly or indirectly related to LID (Barnum et al ., ; Bortolanza et al ., ,b; Dos‐Santos‐Pereira et al ., ; Mulas et al ., ).…”

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

“…Astrocytes and microglia do not constitutively express iNOS but they express the enzyme in pathological conditions such as ischemia, trauma, neurotoxic and inflammatory damage. Several lines of evidence demonstrated that glial NO is involved in the pathophysiology of a variety of neurological diseases including demyelination …”

“…Several lines of evidence demonstrated that glial NO is involved in the pathophysiology of a variety of neurological diseases including demyelination. [29][30][31] As the blood-brain barrier (BBB) normally restricts the access of immune cells from the blood, the brain is traditionally considered as an "immunologically privileged site". However, it is now known that immunological reactions occur in the CNS, particularly during brain inflammation, which differs from inflammation in the periphery because of the relative absence of leukocytes and antibodies.…”