Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation.

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) exhibit microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Here, we report that fluoxetine, one of the most commonly prescribed antidepressants, prevents MPTP-induced degeneration of nigrostriatal DA neurons and increases striatal dopamine levels with the partial motor recovery. This was accompanied by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase; and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. Interestingly, fluoxetine was found to protect DA neuronal damage from 1-methyl-4-phenyl-pyridinium (MPP(+)) neurotoxicity in co-cultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present in vivo and in vitro findings show that fluoxetine may possess anti-inflammatory properties and inhibit glial activation-mediated oxidative stress. Therefore, we carefully propose that neuroprotection of fluoxetine might be associated with its anti-inflammatory properties and could be employed as novel therapeutic agents for PD and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

Prothrombin kringle-2-induced oxidative stress contributes to the death of cortical neurons in vivo and in vitro: role of microglial NADPH oxidase.

In the present study, we examine whether prothrombin kringle-2 (pKr-2), a domain of prothrombin distinct from thrombin and a potent microglial activator induces reactive oxygen species (ROS) generation through stimulation of microglial NADPH oxidase activity, and whether this phenomenon contributes to oxidative damage and consequent neurodegeneration. Intracortical injection of pKr-2 caused significant loss of cortical neurons in vivo after seven days, as evident from Nissl staining and immunohistochemical analysis using the neuronal-specific nuclear protein (NeuN) antibody. In parallel, pKr-2-activated microglia and ROS production were observed in rat cortex displaying degeneration of cortical neurons. Reverse transcription-PCR at various time points after pKr-2 administration disclosed early and transient expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines, such as interleukin 1beta (IL-1beta). Co-localization of iNOS, IL-1beta, and TNF-alpha within microglia was evident with double-label immunohistochemistry. Additionally, pKr-2 induced upregulation of cytosolic components of NADPH oxidase (p67(phox)), translocation of cytosolic p67(phox) protein to the membrane, and p67(phox) expression in microglia in the cortex in vivo, signifying NADPH oxidase activation. The pKr-2-induced oxidation of proteins and loss of cortical neurons were partially inhibited by DPI, an NADPH oxidase inhibitor, and trolox, an antioxidant. Consistent with our hypothesis, following treatment with pKr-2 in vitro, neurotoxicity was detected exclusively in co-cultures of cortical neurons and microglia, but not in microglia-free neuron-enriched cortical cultures, indicating that microglia are required for pKr-2 neurotoxicity. Our results strongly suggest that pKr-2 as an endogenous compound participates in cortical neuron death through microglial NADPH oxidase-mediated oxidative stress.

Roles of transient receptor potential vanilloid subtype 1 and cannabinoid type 1 receptors in the brain: neuroprotection versus neurotoxicity.

Transient receptor potential vanilloid subtype 1 (TRPV1), also known as vanilloid receptor 1 (VR1), is a nonselective cation channel that is activated by a variety of ligands, such as exogenous capsaicin (CAP) or endogenous anandamide (AEA), as well as products of lipoxygenases. Cannabinoid type 1 (CB1) receptor belongs to the G protein-coupled receptor superfamily and is activated by cannabinoids such as AEA and exogenous Delta-9-tetrahydrocannabinol (THC). TRPV1 and CB1 receptors are widely expressed in the brain and play many significant roles in various brain regions; however, the issue of whether TRPV1 or CB1 receptors mediate neuroprotection or neurotoxicity remains controversial. Furthermore, functional crosstalk between these two receptors has been recently reported. It is therefore timely to review current knowledge regarding the functions of these two receptors and to consider new directions of investigation on their roles in the brain.