Beschreibung:
<jats:p> <jats:bold>Abstract:</jats:bold> The neuropathology of Parkinson's disease is reflected in
experimental animals treated with the selective nigrostriatal dopaminergic
neurotoxin MPTP. Neurons exposed to MPTP (MPP<jats:sup>+</jats:sup>) express
morphological features of apoptosis, although the intracellular pathways that
produce this morphology have not been established. The c‐Jun
NH<jats:sub>2</jats:sub>‐terminal kinase (JNK) signaling cascade has been implicated as
a mediator of MPTP‐induced apoptotic neuronal death based on the ability of
CEP‐1347/KT‐7515, an inhibitor of JNK activation, to attenuate MPTP‐induced
nigrostriatal dopaminergic degeneration. In these studies, MPTP‐mediated
activation of the JNK signaling pathway was assessed in the nigrostriatal
system of MPTP‐treated mice. MPTP elevated levels of phosphorylated JNK and
JNK kinase (MKK4; also known as SEK1 or JNKK), by 2.5‐ and fivefold,
respectively. Peak elevations occurred soon after administration of MPTP and
coincided with peak CNS levels of MPP<jats:sup>+</jats:sup>. Increased MKK4
phosphorylation, but not JNK phosphorylation, was found in the striatum,
suggesting that activation of MKK4 occurs in injured dopaminergic terminals.
Both JNK and MKK4 phosphorylations were attenuated by pretreatment with
<jats:italic>l</jats:italic>‐deprenyl, indicating that these phosphorylation events were
mediated by MPP<jats:sup>+</jats:sup>. Moreover, CEP‐1347/KT‐7515 inhibited MPTP‐mediated MKK4 and JNK signaling at a dose that attenuates MPTP‐induced dopaminergic loss. These data implicate this signaling pathway in MPTP‐mediated nigrostriatal dopaminergic death and suggest that it may be activated in the degenerative process in Parkinson's disease.</jats:p>