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Malaria, Anti Malarial Drugs and the Role of Melatonin Send Orders of Reprints at [email protected] Infectious Disorders – Drug Targets, 2012, 12, 371-379 371 Malaria, Anti Malarial Drugs and the Role of Melatonin Venkataramanujam Srinivasan1, Mahaneem Mohamed2, Rahimah Zakaria2 and 2 Asma Hayati Ahmad 1Sri Sathya Sai Medical Educational and Research Foundation Medical Sciences Research Study Center, Prasanthi Nilayam, 40-Kovai Thirunagar, 641014,Tamilnadu, India; 2Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian Kelantan, Malaysia Abstract: Malaria, one of the most deadly diseases of our time affects more than 200 million people across the globe and is responsible for about one million deaths annually. Until recently Plasmodium falciparum has been the main cause for malarial infection in human beings but now Plasmodium knowlesi from Malaysia remains as one of the most virulent parasite spreading fast not only in Malaysia but in different parts of the world. Hence there is urgent need for the global fight to control malaria. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria infected patients with anti-malarial drugs has helped to eliminate malarial infections suc- cessfully but with increased resistance displayed by malarial parasites to these drugs there is resurgence of malaria caused both by drug resistance as well as by infection caused by new malarial species like Plasmodium knowlesi. With recent ad- vances on molecular studies on malarial parasites it is now clear that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence treatment modalities that can effectively block the action of melatonin on Plasmodium species during night time by way of using ei- ther bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating ma- larial infection in man. Keywords: Malaria, anti-malarial drugs, Plasmodium knowlesi, melatonin, Luzindole INTRODUCTION ervoirs [2]. In the absence of transmission blocking vaccine (TBV), primaquine is the only available effective anti malar- Malaria, one of the most severe global infectious diseases ial drug that has gametocytocidal property [7. As screening is caused by a group of parasites from the genus Plasmodium of asexual blood stages of P. falciparum is considered as by one of the five different species namely P. falciparum, P. much more successful than molecular-target-based ap- Vivax, P. malariae, P. ovale and P. knowlesi. Among these proaches, new drug developments are based on this line of parasites, P. falciparum is the most dangerous and devastat- approach. The ongoing strategy for development of trans- ing one resulting in large number of deaths. According to mission blocking drugs (TBD) rests primarily on blood recent World of Health (WHO) report, more than 220 mil- scizonticides that act effectively against late stage of game- lion cases of malarial infections are reported every year with tocytes [7]. The goal of anti malarial drug therapy by should annual mortality rate of 781,000 showing thereby the urgent be directed to reduce the disease and death by targeting necessity of attending to this global problem with immediate blood stage parasites and in the case of P. flaciparum it re- attention [1]. Malaria is characterized by high fever, head- quires elimination of all persistent asexual blood stage forms ache, vomiting, chillness, shaking and anaemia. The control and the long-lived mature stage V, P. falciparum gameto- and management of malaria rests mainly on chemotherapy. cytes, responsible for transmission [8]. Studies conducted on The classical anti malarial drugs that are used include artem- Balb/C mice that luzindole, the antagonist to the pineal hor- isinin, pyronariidine, lumefantine, piperquine, chloroquinine, mone melatonin inhibited the number of trophozoites [9]. In mefloquine, pyrimethamine, atovaquone [2]. But with in- this review paper clinical features of malaria, malarial para- creasing resistance to these drugs there is need for the devel- site cell biology, anti malarial drugs, resistance to antimalar- opment and application of new innovative approaches and ial drugs, development of novel drugs, role of pineal hor- introduction of novel drugs with greater efficacy for the pos- mone melatonin in the growth and differentiation of malarial sible control and eradication of this disease [3]. The drugs parasites and possible use of anti melatonergic procedures that target the hepatic and sexual forms of malarial parasite and drugs for elimination of malarial parasites from the include artemisinin [4], primaquine [5], and artemisinin blood of the infected host will be discussed. combination therapies [6] etc. As Plasmodium sporozoites reach the mammalian within minutes after being released MOLECULAR BIOLOGY OF PLASMODIUM LIFE into the host’s blood by the infected female Anopheles mos- CYCLE quito, the drugs that act on the parasitic stages in the liver is The sporozoites that are injected into humans by a female suggested to eliminate the cryptic hypnozoite infection res- Anopheles mosquito are taken up into the liver and infect the hepatocytes. These parasites develop to form exo- *Address correspondence to this author at the Sri Sathya Sai Medical Edu- erythrocytic schizonts which give rise to several thousands cational and Research Foundation, Prasanthi Nilayam, 40-Kovai Thirunagar, of merozoites. With the rupture of liver cells merozoites are 641014, India; Cell: 0091 9790360432; E-mail: [email protected] released into the blood stream and they invade erythrocytes. 2212-3989/12 $58.00+.00 © 2012 Bentham Science Publishers 372 Infectious Disorders – Drug Targets, 2012, Vo l. 12, No. 5 Srinivasan et al. The intra erythrocytic parasites replicate synchronously and tonin as essential for synchronous maturation of Plasmodium some merozoites infecting the red blood cell (RBC) develop and its survival in the host [24]. into male and female gametocytes. These constitute the later stages of P. falciparum infection. The gametocytes are taken UBIQUITIN PROTEOSOME SYSTEM AND ITS IM- up into the female mosquito gut during the blood meal. The PORTANCE male gametocytes are activated (ex-flagellation) and form gametes which fuse with the female gametes to form diploid Egress, the parasite’s emergence from host erythrocytes ookinetes. These ookinetes migrate to the midgut of the in- involves a co-ordinated event of rupture of parasitophorous sect pass through the gut wall to form oocysts. Following the membrane (PVM) and the erythrocyte membrane (EM) and meiotic division sporozoites are formed which then migrate many proteases like aspartic proteases, cystein proteases, and to the salivary glands of the mosquito, ready for transmission a series of Serine Repeat Antigens (SERAs) are involved in into humans [10]. this process [25]. Proteases like PfCalp in P. falciparum are essential for optimal growth of the parasite and cell cycle Of these various stages outlined above, residence in the progression [26]. These proteases are the targets of anti ma- human erythrocyte is essential for the life cycle for all Plas- larial drugs due to their involvement in parasite development modium that infect man and it is this phase of the life cycle and invasion [27]. The most important protease system in P. that causes disease also. All the clinical symptoms of malaria falciparum is the ubiquitin-proteosome protein degradation like fever, anaemia, neurological manifestations are associ- system (UPS) which is responsible for degrading unwanted ated with blood stage of the Plasmodium life cycle [11]. or misfolded proteins and thereby playing an important role With the introduction of new genetic and molecular tools in cell cycle regulation. The UPS pathway in P. falciparum and imaging technology, many exciting discoveries have has been deduced by Dr Hagai Ginsburg been made in the biology of growth and development of (http://sites.huji.ac.iL/malaria/maps/proteaUbiqpath.html) Plasmodium. Genome sequencing projects have been suc- and is suggested to carry out functions specific to pathogene- cessfully completed for P. falciparum and other species sis or virulence [25]. Recent studies show that pineal hor- [12,13,14]. It is suggested that progression of the malaria mone melatonin up regulates genes related to Ubiq- parasite life cycle involves interplay between the parasite’s uitin/proteosome system which is inhibited by melatonin changing environment and its own built in genetic pro- antagonist luzindole [28]. The effects of melatonin on UPS gramme [15]. Examination of the P. falciparum proteome transcription modulation is mediated by a protein kinase detected more than 900 proteins in gametocytes, and out of known as PfPK7, a P. falciparum orphan kinase that causes these 315 are found exclusively in gametocytes. Nearly 97 increase in cytosolic calcium, and up regulation of UPS proteins identified are gamete specific [16]. The absence of genes [28].The signalling pathways in Plasmodium is fun- sex chromosomes in malarial parasites and the presence of damental to the development of new drugs to control ma- gametocyte specific and sex specific genes found dispersed laria. Nearly 20 to 30% of the drug discovery programme in amongst 14 chromosomes raises many unsolved questions most pharmaceutical companies focuses on protein kinases regarding the molecular mechanism
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