The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Abstract

In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 in order to explore its potential neuroprotective effects in models of Parkinson’s disease (PD) and the potential mechanism(s) underlying such properties. Pretreatment with D-512 in vitro was found to rescue rat adrenal phaeochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA) administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pretreatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), including losses in striatal dopamine (DA), reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for PD.

Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure–Activity Relationship Study of N6-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson’s Disease

“…26–36 Some of our lead multifunctional D 2 /D 3 agonist molecules, such as ( S )- N 6 -(2-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)ethyl)- N 6 -propyl-4,5,6,7-tetrahydrobenzo[ d ]thiazole-2,6-diamine (D-264) and 1 (D-512) (Figure 1), exhibited neuroprotection in in vitro and in vivo experiments. 30,33,34 Additionally, we have reported development of multifunctional brain penetrant iron chelators with agonist activity at D 2 /D 3 receptors. 29,31 …”

“…32 As the compound turned out to be a promising candidate for PD through a number of experiments, 33,34 we further wanted to delve into a comprehensive structure−activity relationship (SAR) study and accordingly introduce, in the current work, several indole derivatives on the piperazine ring with varying chain length and position of attachment in the indole aromatic ring. We have also introduced a propargyl group in our core hybrid structure to shed light on its role in interacting with DA D 2 /D 3 receptors.…”

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo

“…Treatment of PC12 cells with 6-OHDA for 24 h resulted in significant, dose-dependent neurotoxicity as indicated by a significant decrease (∼ 50%) in cells exposed to 75 μM 6-OHDA; this concentration was used in subsequent in vitro experiments (also see Fig. 5a, Shah et al, 2014). The potential neuroprotective effect of D-607 on 6-OHDA-induced toxicity was evaluated following pre-treatment with the drug.…”

“…As of now, no neuroprotective drugs have been identified or approved by the FDA for the treatment of PD. The overall goal of our research is to develop orally active multifunctional treatment agents to address both symptomatic (relieving motor dysfunction) and disease-modifying neuroprotective effects to slow or stop the progression of the disease (Das et al, 2015; Ghosh et al, 2010; Li et al, 2010; Modi et al, 2014; Santra et al, 2013; Shah et al, 2014). A number of iron chelators have been employed in the preclinical and clinical studies of PD (Devos et al, 2014; Grolez et al, 2015).…”

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].…”