Parkinson’s disease (PD) is second only to Alzheimer’s disease (AD) as the most common and debilitating age-associated human neurodegenerative disorder. A host of environmental, genetic, and immune cues have been associated with the onset of this disease . Clinical symptoms of PD include tremor, bradykinesia, rigidity, and postural instability [2, 3]. Pathologically, it is characterized by gliosis and progressive degeneration of the dopaminergic neurons associated with the presence of intracytoplasmic inclusions (Lewy bodies) in the substantia nigra pars compacta (SNc) [2, 3]. The symptoms of PD can be alleviated by drugs that enhance dopamine function, among which L-dopa is considered the most effective one. However, L-dopa fails to halt the progression of PD. Aside from having undesirable side effects, such as motor fluctuations and dyskinesias, the therapeutic effect of L-dopa diminishes after about two years of treatment . Moreover, long term use of L-dopa may actually damage neurons, accelerating neuronal apoptosis. Since programmed cell death plays a key role in the neurodegenerative processes in PD , new generation of neuroprotective agents against apoptosis may improve the prognosis of PD.
Curcumin has been implicated to be neuroprotective in a variety of neurodegenerative disorders such as AD and cerebral ischemi [6, 7]. Epidemiological evidence from India has related the huge consumption of turmeric (curcumin is its essential component) to its lowest prevalence rates of AD and PD in the world . As a matter of fact, curcumin is now in Phase II clinical trials for AD . Curcumin has been reported to be a good inhibitor of c-Jun N-terminal kinase (JNK) mediated gene transcription . JNK is a important member of mitogen-activated protein kinases (MAPK) family, which can be activated by a variety of stimuli including neurotoxic insults, environmental stress and apoptotic agents [11–13]. JNK is composed of three different isoforms, JNK1, JNK2 and JNK3. In contrast to JNK1 and JNK2, which are ubiquitously expressed, JNK3 is largely restricted to the brain and is most consistently associated with neuronal death  Our previous studies and others suggested that JNK plays an important role in mediating MPTP-induced neurotoxicity. CEP1347, a specific JNK pathway inhibitor, attenuates the loss of nigrostriatal dopaminergic neurons after the exposure to MPTP  SP600125 (a selective inhibitor of JNK) prevents dopaminergic neurons from death and decreases the loss of catecholamines in the striatum  by partially inhibiting JNK pathway. Therefore, it is reasonable to assume that blockade of JNK pathway may prevent or effectively slow down the progression of PD. Nevertheless, an understanding of the molecular mechanisms by which JNK regulates apoptosis should provide insights into the treatment of PD.
Previous studies demonstrated that JNK can promote cell death by regulating the activation of substrates, such as Bcl-2 family members . The Bcl-2/Bax heterodimer is the active component for death protection [18, 19]. Phosphorylation of Bcl-2 may possibly release Bax from Bcl-2/Bax dimmers [20–22]. The preapototic protein Bax forms pores in the outer mitochondrial membrane to release cytochrome c , thus promoting apoptosis,. On death induction, cytochrome c not only translocates into the cytosol, but furthermore can be abundantly detected in the extracellular medium. Thus, release of cytochrome c is considered as an indication of mitochondrial dysfunction . It is therefore possible that through regulating the activation of some Bcl-2 family members, activated JNK pathway increase mitochondrial membrane permeability and the subsequent release of apoptogenic factors, which could ultimately contribute to mitochondria mediated apoptosis.
Whether curcumin could inhibit the abnormal activation of JNK induced by MPTP, thus prevent the triggering of a series downstream effects that lead to apoptosis is unknown. In this study, the inhibitory effect of curcumin to the MPTP-induced activation of JNK was evaluated. Using a MPTP-induced PD mice model, we demonstrated that curcumin could suppress the activation of the JNK in PD mice induced by MPTP. Furthermore we demonstrated that curcumin could decrease MPTP-induced injuries to dopaminergic cell bodies and terminals via inhibiting mitochondria mediated apoptosis.