Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents

Abstract

Recent studies provide evidence that phospholipase A₂ (PLA₂) may play a role in the development of experimental parkinsonism. In this investigation an attempt was made to determine a possible protective effect of quinacrine (QNC), a PLA₂ inhibitor on MPTP as well as 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in rodents. For MPTP studies, adult male mice (C57 BL) were treated with MPTP (30 mg/kg, i.p.) daily for 5 days. QNC was injected i.p. in the doses of 0, 10, 30 and 60 mg/kg daily 30 min before MPTP in four different groups. Two other groups of mice received either vehicle (control) or a high dose of QNC (60 mg/kg). Two hours after the last injection of MPTP, striata were collected for the analysis of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and glutathione (GSH). For the 6-OHDA study, male Wistar rats were infused with 6-OHDA (60 μg) in the right striatum under chloral hydrate anesthesia. The rats in different groups were treated with 0, 5, 15 and 30 mg/kg QNC (i.p.) for 4 days, while first injection was given 30 min before 6-OHDA. On day 5, rats were sacrificed and striata were stored at −80°C. Administration of MPTP or 6-OHDA significantly reduced striatal DA, which was significantly attenuated by QNC. Concomitant treatment with QNC also protected animals against MPTP or 6-OHDA-induced depletion of striatal GSH. Our findings clearly suggest the role of PLA₂ in MPTP and 6-OHDA induced neurotoxicity and oxidative stress. However, further studies are warranted to explore the therapeutic potential of PLA₂ inhibitors for the treatment of Parkinson’s disease.

Introduction

Parkinson’s disease (PD) is a commonly occurring neurodegenerative disorder that produces muscular rigidity, bradykinesia, tremor of resting limbs and loss of postural balance [44]. The basic neuropathology of PD involves degeneration of pigmented neurons in substantia nigra resulting in depletion of dopamine (DA) and its metabolites 23, 32. The discovery of the two neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with the ability to destroy DA-producing cells in substantia nigra in animals has overwhelmingly accelerated the pace of research in the field of PD. Peripheral administration of MPTP in C57 black mouse and intrastriatal injection of 6-OHDA in rat have been widely used as convenient and acceptable models for the induction of experimental parkinsonism 3, 12, 13, 29, 57.

The agents with the ability to interfere with the synthesis, release, uptake, metabolism, or drug-receptor interaction of DA have been shown to alter the course of experimental parkinsonism 4, 11, 24, 46, 72, 76. Recently, a direct role of phospholipase A₂ (PLA₂) in regulation of DA release from neuronal cells has been suggested [36]. Intracerebral injection of PLA₂ enzyme has been shown to significantly reduce DA-mediated rotational behavior in rats indicating the long-lasting inhibition of nigrostriatal dopaminergic pathways 9, 10. Furthermore, Klivenyi et al. [34] observed that mice deficient in cytosolic PLA₂ are resistant to MPTP neurotoxicity suggesting the role of this enzyme in the etiopathology of Parkinson’s disease. Enhanced activity of PLA₂ has also been observed in several neurological conditions including cerebral ischemia 6, 15, stroke 21, 56, neurotrauma 5, 22, epileptic seizures [18], schizophrenia 25, 60 and Alzheimer’s disease 19, 68. These studies point towards a possible beneficial effect of PLA₂ inhibitors for the treatment of neurodegenerative disorders.

Quinacrine (QNC, also known as mepacrine) is an acridine derivative, which was widely used during World War II as an antimalarial agent [59]. It is a cell membrane stabilizer and a potent inhibitor of PLA₂ [75]. Recently, QNC has been shown to predominantly block the activity of PLA₂ in neurons [71]. Peripheral injection of QNC is considered to be one of the most suitable methods for inhibiting PLA₂ in the central nervous system [58]. Besides preventing PLA₂-related pathophysiological mechanisms, QNC has also been shown to downregulate production of oxygen-derived free radicals (ODFR) and reduce oxidative stress-mediated cellular toxicity 1, 70. The present investigation was conducted to study the effect of QNC on 6-OHDA- and MPTP-induced neurotoxicities in rodents.