Cabergoline, Dopamine D2 Receptor Agonist, Prevents Neuronal Cell Death under Oxidative Stress via Reducing Excitotoxicity

Abstract

Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H2O2 exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H2O2 was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H2O2, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca2+ channel demonstrated a survival effect against H2O2. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H2O2.

Original article Cabergoline protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture

“…Sulpiride also abolished the protection of dopaminergic neurons by ropinirole against 6-OHDA [9]. In SHSY-5Y cells expressing D 2 receptors the protective effect of cabergoline against paraquat toxicity was partially reduced by inhibition of the D 2 receptor with clozapine [1], and recently it was shown that in cortical neurons cabergoline prevented cell death induced by H 2 O 2 through a D 2 receptor-mediated mechanism [18]. In contrast, the protection of THir neurons against rotenone toxicity by cabergoline appears independent of dopamine receptor stimulation.…”

“…Yoshioka et al reported that cabergoline normalized the dopamine turnover in the striatum of 6-OHDA-treated mice [32]. Finally, in cultures of cortical neurons cabergoline prevented H 2 O 2 -induced neuronal cell death by reducing excitotoxicity [18].…”

Neuroprotective effects of Peltophorum pterocarpum leaf extract against hydrogen peroxide induced oxidative stress and cytotoxicity

“…Nevertheless, it is also activated in some neuronal cells under H 2 O 2 induced oxidative stress [47]. The effect of ERK1/ 2 activation on the pro-survival or pro-apoptotic roles in the cells depends on the kinetics, duration, stimulus and cell type [42,48,49].…”

“…In primary cortical cells, H 2 O 2 was reported to have activated both ERK1/ 2 and p-38 MAP kinase signaling protein in a concentration and time dependent manner [49]. Studies on plant bioactives such as kukoamine B and loganin in human neuroblastoma ShSy5y cells, have been reported to provide neuroprotection against H 2 O 2 induced oxidative stress via attenuation of phospho-ERK1/2 [50,51].…”

Carriers of a common variant in the dopamine transporter gene have greater dementia risk, cognitive decline, and faster ventricular expansion

“…Monoamine oxidase B (MAO-B) inhibitors can prevent neuronal loss by inducing neuroprotective genes, anti-oxidant enzymes, and redox proteins [45]. In addition, some dopamine D2/D3 receptor agonists block neuronal cell death under oxidative stress [46], and protect against glutamate toxicity via inactivation of pro-apoptotic factors [47] and up-regulation of glutamate transporters [48]. Moreover, dopamine plays an important role in neuroplasticity [49–51], and activation of D1/D5 receptors can prevent the internalization of AMPA and NMDA receptors caused by oligomeric amyloid- beta (Aβ) peptides [52], suggesting that increased DA transmission may protect against Aβ-mediated impairments in synaptic plasticity and their neurotoxic repercussions [53–55].…”