Abstract
BackgroundParkinson’s disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits but also to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. In the inflammatory tissue, cyclooxygenase (COX) is upregulated leading to an ongoing inflammatory process such as prostaglandin-mediated increased cytokine levels. Therefore, inhibition of COX by indomethacin may prevent the inflammatory response and the impairment of adult hippocampal neurogenesis.MethodsWildtype C57Bl/6 and transgenic Nestin-GFP mice were treated with MPTP followed by short-term or long-term indomethacin treatment. Then, aspects of inflammation and neurogenesis were evaluated by cell counts using immunofluorescence and immunohistochemical stainings in the SN and dentate gyrus (DG). Furthermore, hippocampal mRNA expression of neurogenesis-related genes of the Notch, Wnt, and sonic hedgehog signaling pathways and neurogenic factors were assessed, and protein levels of serum cytokines were measured.ResultsIndomethacin restored the reduction of the survival rate of new mature neurons and reduced the amount of amoeboid CD68+ cells in the DG after MPTP treatment. Indomethacin downregulated genes of the Wnt and Notch signaling pathways and increased neuroD6 expression. In the SN, indomethacin reduced the pro-inflammatory cellular response without reversing dopaminergic cell loss.ConclusionIndomethacin has a pro-neurogenic and thereby restorative effect and an anti-inflammatory effect on the cellular level in the DG following MPTP treatment. Therefore, COX inhibitors such as indomethacin may represent a therapeutic option to restore adult neurogenesis in PD.
Highlights
Parkinson’s disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits and to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits
We studied the influence of indomethacin on different stages of adult hippocampal neurogenesis after MPTP treatment to test whether a therapy with indomethacin could be a suitable strategy to restore adult neurogenesis in PD patients
As MPTP treatment itself is accompanied by inflammatory reactions on the cellular level in the hippocampus [22, 23], we suggest a pro-neurogenic effect by indomethacin treatment based on an anti-inflammatory effect on the cellular level
Summary
Parkinson’s disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits and to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. A commonly used animal model of the disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model It represents the characteristic dopaminergic cell loss in the SN, determining the onset of PD [14, 15]. In the SN, dopaminergic neurodegeneration leads to a release of soluble neuron-injury factors, which activate microglia [16, 17] This results in the release of neurotoxic agents such as cytokines, reactive oxygen species, nitric oxide radicals, and prostaglandins (PG) and attracts lymphocytic infiltration of CD4+ and CD8+ T cells [17, 18]. All these events lead to a perpetuation of inflammation and neurodegeneration in the SN [17,18,19,20,21]
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