Histamine modulates nitric oxide release by microglia and dopaminergic neuronal survival

Microglia cells, the resident immune cells in the brain, play a critical role in the development and progression of several neurodegenerative diseases. Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons (DA) in the substantia nigra (SN), striatal dopamine depletion and motor impairments. Accumulating clinical and experimental evidences suggest that neuroinflammation plays a critical role in the pathogenesis of PD through the activation of microglia cells and the subsequent production of a vast array of inflammatory mediators, including nitric oxide (NO). Histamine (HIS), an amine that acts as a neurotransmitter and inflammatory mediator, has been reported to play a role in the pathogenesis of PD. Indeed, alterations in the histaminergic innervations in the striatum and SN and increased histamine concentrations in the blood, striatum and SN were found in PD patients. Based on these data, our aim was to uncover the effects of histamine on microglia cells derived from the SN of Wistar rats and then evaluate whether soluble factors released by microglia previously stimulated with histamine could modulate dopaminergic neuronal survival. Firstly, microglia cell cultures were used to study the effects of HIS and its receptors on NO production, which was measured by the Griess assay. We demonstrated that HIS triggered an increase of NO production as compared with control, an effect mediated by histamine H4 receptor (H4R) activation. Interestingly, in the presence of an inflammatory context, mimicked by lipopolysaccharide (LPS), HIS inhibited LPS-induced NO production not only by H4R but, possibly through histamine H1 receptor (H1R) activation. Then, conditioned medium derived from microglia cells (MCM) challenged with HIS and/or LPS was collected to evaluate its effects on the viability of DA neurons present in neuron-astrocyte midbrain co-cultures. In fact, conditioned medium derived from microglia cells exposed to LPS or HIS induced a decrease in the number of Tyrosine Hydroxylase positive neurons; whereas this noxious effect was abolished when MCM obtained from microglia challenged with HIS plus LPS was used. Curiously, the same effects were observed when HIS and/or LPS were added directly on neuron-astrocyte midbrain co-cultures. Together, our results suggest that HIS per se acts as a pro-inflammatory mediator, whereas, in an inflammatory context, HIS has a putative anti-inflammatory profile that can protect dopaminergic neurons