Synergistic effect of α-dihydroergocryptine and L-dopa or dopamine on dopaminergic neurons in primary culture

Abstract

There is an ongoing controversy about potential toxicity of L-3,4-dihydroxyphenylalanine (L-dopa) to dopaminergic neurons in Parkinson's disease (PD). Neuroimaging data suggest that L-dopa accelerates the loss of dopamine nerve terminals, especially at higher doses. The disputed aspect of toxicity and the frequently observed motor complications accompanying L-dopa therapy have led to an increased use of dopamine agonists during the past two decades. Reports describing their neuroprotective potential to dopaminergic neurons have attracted much attention. Here, we describe the novel finding that the combination of a dopamine (DA) agonist, alpha-dihydroergocryptine (DHEC), with L-dopa or DA exerts a synergistic stimulatory effect on dopaminergic neurons in primary culture, while each substance alone had no or less effect. DA receptor stimulation plays a decisive role. The synergistic effect suggests that a combinatory therapy can be beneficial to slow the degeneration of dopaminergic neurons.

Original article Neuroprotective effect of rotigotine against complex I inhibitors, MPP+ and rotenone, in primary mesencephalic cell culture

“…These results are similar to those achieved with the D 2 receptor ago nist αdihydroergocryptine that showed no stimula tion of THir neurons, but differ from the D 2 receptor agonist lisuride which significantly enhanced the number of THir neurons under the same treatment conditions [9,11]. Treatment with 10 µM rotigotine decreased the number of THir neurons, which is similar to the behaviour of the D 2 agonist pergolide and αdihydroergocryptine [9,10]. However, the high unphysiological concentration of 10 µM exceeds by far the therapeutic doses of 116 mg/day and the achieved plasma concentrations of unconjugated rotigotine which amount up to 1 ng/ml [7].…”

“…In a concentration range up to 1 µM, rotigo A B tine, when given for eight consecutive days, did not affect the survival of THir neurons. These results are similar to those achieved with the D 2 receptor ago nist αdihydroergocryptine that showed no stimula tion of THir neurons, but differ from the D 2 receptor agonist lisuride which significantly enhanced the number of THir neurons under the same treatment conditions [9,11]. Treatment with 10 µM rotigotine decreased the number of THir neurons, which is similar to the behaviour of the D 2 agonist pergolide and αdihydroergocryptine [9,10].…”

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

“…1A). Such a stimulatory effect is not exhibited by all ergoline dopamine agonists, since it was for example demonstrated for lisuride [6], but not for pergolide [5] or α-dihydroergocryptine [4] when analogously used under the same treatment conditions. Similarly to these ergoline agonists, cabergoline reduced the number of dopamine neurons at an unphysiological high concentration (10 µM).…”

“…For instance, blocking of dopamine D 2 receptors by the dopamine receptor antagonist sulpiride prevented dopaminergic neuroprotection by lisuride and α-dihydroergocryptine against glutamate and dopamine, respectively [4,17]. Sulpiride also abolished the protection of dopaminergic neurons by ropinirole against 6-OHDA [9].…”

“…Cabergoline is an ergot-derived dopamine agonist with high affinity for the dopamine D 2 receptor, but also possesses significant affinity for the D 3 and D 4 receptor. It has the longest half-life among related dopamine agonists [15].…”