Inflammation is associated with the neuropathology of neurodegenerative disorders such as Parkinson┐s disease (PD). Excessive microglial activation and the increase of pro-inflammatory cytokines, such as interleukin-1b (IL-1b), have been associated with exacerbated cell death in patients and models of PD. Members of the mitogen-activated protein (MAP) kinase pathway, p38 and JNK, mediate the death of dopaminergic (DA) neurons in response to inflammatory stress-signals. This pathway is inhibited by the dual-specificity mitogen-activated protein kinase phosphatase1 (MKP-1) through dephosphorylation of tyrosine and threonine residues of activated kinases. Over-expression of MKP-1 has been shown to protect non-neuronal cells from apoptosis through its ability to dephosphorylate p38 and JNK. 6-hydroxydopamine (6-OHDA) treatment of DA neuronal-enriched cultures causes a decrease in the intensity of fluorescence of MKP-1, accompanied by an increase in p38 activity (Nolan & Long- Smith, unpublished data). This study assessed the effect of an inflammatory environment (IL-1b) and the DA neurotoxin, 6-OHDA, on ventral mesencephalic neural precursor cell (VMNPC) proliferation and differentiation. Sprague┐Dawley rat ventral mesencephalic tissue was isolated at embryonic (E) day 14 and VMNPCs were proliferated as neurospheres for 7 days in vitro (DIV) with appropriate mitogens. Cells were treated with IL-1b (10 ng/ml) on the day of seeding and every 2┐3 days for 7 days and with 6-OHDA (40 lM) at 7DIV for 30 min. At 7DIV neurospheres were dissociated and allowed to differentiate for a further 7DIV during which time cells were treated with IL-1b (10 ng/ml) on the day of seeding and every 2┐3 days for 7 days and with 6-OHDA (40 lM) at 14DIV for 30 min. Cells were immunocytochemically stained for nestin to label neural progenitor cells, doublecortin (DCX) to label newly-born neurons and glial fibrillary acidic protein (GFAP) to label astrocytes. IL-1b and 6-OHDA alter the expression of MKP-1 + nestin + , GFAP + and DCX + cells both during proliferation and differentiation. MKP-1 is a possible key modulator of DA neuronal survival both in response to DA neurotoxins and exposure to an inflammatory environment and could be a possible therapeutic target for the treatment of PD.