Evaluating plasmodium berghei infection influence and asiaticacid administration efficacy in sprague dawley male rats: effects on parasitamia, glucose homeostasis and renal electrolyte handling.

Doctoral Degree. University of KwaZulu-Natal, DurbanAbstract Introduction: Five human-infecting Plasmodium species orchestrate varied pathophysiology culminating in malaria. Despite being treatable, malaria has high mortality and morbidity in pregnant women and children under five years. Current treatment is hampered by drug resistance, toxicity and failure to address malaria induced pathology directly. Asiatic acid has antioxidant, pro-oxidant, antihyperglycaemiac renoprotective qualities which may be anti-disease properties in malaria. Very little is currently known or reported about these asiatic acid anti-disease perspectives in malaria and therefore require further investigations. The aim of this study was to investigate the influence of asiatic acid administration and malaria infection on parasitaemia suppression, glucose homeostasis, renal function and electrolyte handling in Plasmodium berghei-infected Sprague Dawley male rats. Methods: Three sub-chronic studies and one acute study were conducted. The sub-chronic protocol involved per-oral pre- and post-infection administration of asiatic acid (5, 10, 20 mg/kg) and post-infection transdermal drug delivery system application of asiatic acid (5, 10, 20 mg/kgamidated hydrogel matrix pectin patch). Acute studies included post-infection oral glucose tolerance response to asiatic acid. Influence of asiatic acid on %parasitaemia changes, physicochemical changes, immunological effects of malaria, haematological results of malaria, antioxidant capacity, glucose homeostasis, renal function and renal electrolyte handling were investigated. Results: Asiatic acid suppressed parasitaemia to varying extents with asiatic acid 10mg/kg and 5mg/kg emerging as the most efficacious amongst the three doses by per oral administration and transdermal delivery drug delivery system, respectively. Malaria suppression occurred in both pre-infection and post-infection administration of asiatic acid. Asiatic acid preserved physicochemical parameters, ameliorated haematological effects of malaria, influenced immunological effects of malaria, modulated glucose homeostasis in malaria, protected renal function and electrolyte handling in malaria. Asiatic acid improved glucose tolerance response in acute malarial states. Antioxidant status was also improved in malaria. Conclusions: Asiatic acid displayed chemoprophylactic and chemotherapeutic effects in malaria. Asiatic acid has both glucose homeostatic and renoprotective properties in malaria. The antioxidant characteristics of the amphiphilic asiatic acid seem to exert anti-disease and antiparasitic effects in malaria. Asiatic acid may be used as an antimalarial compound with ability to ameliorate malaria associated pathophysiology.Abstract available in the PDF

Severe Malarial Anemia (SMA) Pathophysiology and the Use of Phytotherapeutics as Treatment Options

Hemolytic anemia results when red blood cells (RBCs) are destroyed prematurely by a number of agents. Obligate intracellular parasites like the Plasmodium species proliferate by infecting RBCs, growing through different stages of their life cycles, expanding their population to unsustainable numbers and eventually rupturing the cell membranes in order to transmit and infect new RBCs. In this manner, more RBCs are infected by the parasites and destroyed together with some nonparasitized cells. Membranes of RBCs are altered and deformed by parasite antigens expressed on the surfaces of both parasitized and nonparasitized cells, which lead to their premature phagocytosis and destruction by the reticuloendothelial system. Parasites and the hemoglobin waste products produced by them are released when the RBCs burst. Activated leukocytes take up the hemoglobin waste (hemozoin which is a polymerized heme), which stimulates the innate immune system leading to the synthesis and secretion of pro- and anti-inflammatory cytokines, chemokines, growth factors and mediators. Together with the destruction of RBCs in malaria, imbalance between pro- and anti-inflammatory events results in the modification of erythroid cell proliferation leading to severe malarial anemia (SMA) and other pathophysiologies of malaria. While current malarial management is targeted at the destruction of the parasite, it is the malaria-related pathophysiology (disease aspect of malaria) like severe malarial anemia that results in the high malaria morbidity and mortality. Antidisease approaches promise to be more effective at malarial management. Triterpenes with antioxidant, pro-oxidant, anti-inflammatory and antiparasitic effect show effects at retarding and abrogating severe malarial anemia. Asiatic acid, amongst other triterpenes like oleanolic acid, masilinic acid administered through oral or transdermal route improves severe malaria anaemia providing promise in the management of malaria pathophysiology

Malarial Pathophysiology and Phytochemical Interventions: A Current Discourse on Oxidative Stress Anti-Disease Phytotherapeutics

Malarial systemic pathophysiology refers to physiological changes or abnormalities that are experienced by individuals infected with the Plasmodium parasite not be presenting in the absence of active, chronic or previous infection. The pathologies are derived, in part, from OS induced insults whose mediators are readily available in malaria. The malaria disease is equivalent to the pathophysiology as shown by the abnormal syndromic expressions ranging from ailments that affect homeostatic mechanisms and processes to tissues and organ specific damages and derangements. Phytotherapeutic remedies refer to the natural phytochemicals or plant medicinal compounds and their derivatives with known antiparasitic and antimalarial disease effects in both experimental and clinical situations. The chapter explores how Plasmodium infection generates or cause to be generated oxidative stress, how oxidative stress drives systemic disease process and how phytotherapeutics treatment (artemisinins) and administration (asiatic acid) in malaria resolves the various pathologies as a current situational analysis

Malaria Pathophysiology as a Syndrome: Focus on Glucose Homeostasis in Severe Malaria and Phytotherapeutics Management of the Disease

Severe malaria presents with varied pathophysiological manifestations to include derangement in glucose homeostasis. The changes in glucose management by the infected human host emanate from both Plasmodium parasitic and host factors and/or influences which are aimed at creating a proliferative advantage to the parasite. This also includes morphological changes that that take place to both infected and uninfected cells as structural alterations occur on the cell membranes to allow for increased nutrients (glucose) transportation into the cells. Without the availability, effective and efficient intervention there is a high cost incurred by the human host. Hyperglycaemia, hypoglycaemia and hyperinsulinemia are critical aspects displayed in severe malaria. Conventional treatment to malaria renders itself hostile to the host with negative glucose metabolism changes experiences in the young, pregnant women and malaria naïve individuals. In malaria, therefore, host effects, parasite imperatives and treatment regimens play a pivotal role in the return to wellness of the patient. Phytotherapeutics are emerging as treatment alternatives that ameliorate glucose homeostasis alternations as well as combat malaria parasitaemia. The phytochemicals e.g. triterpenes, have been shown to alleviate the “disease” and “parasitic” aspects of malaria pointing at key aspects in ameliorating malaria glucose homeostasis fallings-out that are experienced in malaria

ASIATIC ACID INFLUENCES GLUCOSE HOMEOSTASIS IN P. BERGHEI MURINE MALARIA INFECTED SPRAGUE-DAWLEY RATS

Background: Glucose homeostasis derangement is a common pathophysiology of malaria whose aetiology is still controversial. The Plasmodium parasite, immunological and inflammatory responses, as well as chemotherapeutics currently used cause hypoglycaemia in malaria. Anti-parasitic and anti-disease drugs are required to combat malaria while ameliorating the pathophysiology of the infection. Asiatic acid has anti-hyperglycaemic, antioxidant, pro-oxidant properties useful in glucose homeostasis but its influence in malaria is yet to be reported. Here we present findings on the influence of asiatic acid on glucose metabolism in vivo using P. berghei-infected Sprague Dawley rats. Materials and Methods: Acute as well as sub-chronic studies were carried out in vivo where physicochemical properties and glucose homeostasis were monitored after administration of asiatic acid (10mg/kg) in both non-infected and infected animals. Glucose metabolism associated biochemical changes in malaria were also investigated. Results: In acute studies, asiatic acid improved oral glucose response while in the sub-chronic state it maintained food and water intake and suppressed parasitaemia. Normoglycaemic control was maintained in infected animals through insulin suppression and increasing glucagon secretion, in both acute and chronic studies. Asiatic acid administration curtailed lactate concentration towards normal. Conclusion: Per oral post-infection asiatic acid administration preserved drinking and eating habits, inhibited sickness behaviour while suppressing parasitaemia. Reciprocal relationship between insulin and glucagon concentrations was maintained influencing glucose homeostasis positively and inhibition of hyperlactaemia in malaria

Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation in Severe and Chronic Diseases

Lipid peroxidation is an end process of cellular injury driven by oxidative stress (OS) and inflammation through several molecular changes. Metabolism-generated reactive oxygen species avidly attack the polyunsaturated fatty acids in lipid cell membranes, initiating a self-propagating chain-reaction. Cell membrane destruction, lipids and the end-products of lipid peroxidation reactions are hostile to the viability of cells, even tissues causing and exacerbating Diabetes Mellitus (DM), neurodegenerative disorders (NDDs), cardiovascular diseases (CVDs) and Rheumatoid Arthritis (RA). Current treatment regimens have untoward side effects in the long-term necessitating phytochemical use as these are part of natural food sources. Enzymatic and non-enzymatic antioxidant defense mechanisms may be over run causing lipid peroxidation to take place. In disease states, oxidative stress may increase with subsequent production of increased free radicals which may over run the antioxidant capacity of the body with resultant oxidative damage on polyunsaturated fatty acids in the cell fluid membranes with cellular and tissue damage. Phytochemicals, have been shown to ameliorate diseases through attenuation of oxidative stress, inflammation, lipid peroxidation, causing tissue regeneration by regulating signaling systems and neuroprotective processes. Involvement of polyphenolic and non-phenolic phytochemical in the attenuation of OS, inflammation and lipid peroxidation remain areas of critical importance in combating DM, CVDA, NDD and RA

Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene Phytotherapeutics

Malaria driven pathophysiology inimically conjoined to systemic inflammation response cascade in a vicious feed-forward cycle destined to a terrible debilitation or demise of the host. The Plasmodium parasite initiates physiological changes when it is transmitted into the human host by intermediate host and vector. Sporozoites injection elicits immunological and inflammatory response suppression facilitating movement into the blood stream undetected, destined to hepatocyte. Subsequently, hepatocyte invasion culminates in intracellular growth and conversion of the parasites rapturing hepatocytes releasing merozoites into the extrahepatic circulation. Inflammatory and immunological response initiation results in overt malarial disease symptoms. Initially, inflammatory response alleviates and curtails infection. Activation of leukocytes, lymphocytes, monocytes, and phagocytes secretes inflammatory mediators, chemokines, cytokines cytoadhering molecules which accelerate infection patency. Hormonal processes influence disease tolerance without necessarily interfering with parasitemia. Current treatment is anti-parasitic. Phytotherapeutic intervention in malaria is anti-parasitic and anti-disease effects that terminate the vicious cycle and alleviating disease. The phytochemicals, in malarial experimental and clinical work, include asiatic acid, maslinic acid, oleanolic acid, and inflammatory and immunological aberrations evolving in malaria and the effects of phytochemical therapeutics in the alleviation of the disease to enable leverage of future treatment regimens through harnessing existing plants materials is explored

Asiatic acid-pectin hydrogel matrix patch transdermal delivery system influences parasitaemia suppression and inflammation reduction in P. berghei murine malaria infected Sprague-Dawley rats

Objective: To report the influence of transdermal delivery of asiatic acid (AA) in Plasmodium berghei-infected Sprague Dawley rats on physicochemical changes, %parasitaemia and associated pathophysiology. Methods: A topical once-off AA (5, 10, and 20 mg/kg)- or chloroquine (CHQ)-pectin patch was applied on the shaven dorsal neck region of Plasmodium berghei-infected Sprague Dawley rats (90- 120 g) on day 7 after infection. Eating and drinking habits, weight changes, malaria effects and %parasitaemia were compared among animal groups over 21 d. Results: AA-pectin patch application preserved food and water intake together with %weight gain. All animals developed stable parasitaemia (15%-20%) by day 7. AA doses suppressed parasitaemia significantly. AA 5 mg/kg patch was most effective. AA and CHQ displayed bimodal time-spaced peaks. CHQ patch had a longer time course to clear parasitaemia. Conclusions: AA influences bio-physicochemical changes and parasitaemia suppression in dose dependent manner. In comparison by dose administered, AA has much better efficacy than CHQ. AA may be a useful antimalarial. AA and CHQ displays bimodal peaks suggesting possible synergism if used in combination therap

Asiatic acid influences glucose homeostasis in P. berghei murine malaria infected sprague-dawley rats

Background: Glucose homeostasis derangement is a common pathophysiology of malaria whose aetiology is still controversial. The Plasmodium parasite, immunological and inflammatory responses, as well as chemotherapeutics currently used cause hypoglycaemia in malaria. Anti-parasitic and anti-disease drugs are required to combat malaria while ameliorating the pathophysiology of the infection. Asiatic acid has anti-hyperglycaemic, antioxidant, pro-oxidant properties useful in glucose homeostasis but its influence in malaria is yet to be reported. Here we present findings on the influence of asiatic acid on glucose metabolism in vivo using P. berghei-infected Sprague Dawley rats.Materials and Methods: Acute as well as sub-chronic studies were carried out in vivo where physicochemical properties and glucose homeostasis were monitored after administration of asiatic acid (10mg/kg) in both non-infected and infected animals. Glucose metabolism associated biochemical changes in malaria were also investigated.Results: In acute studies, asiatic acid improved oral glucose response while in the sub-chronic state it maintained food and water intake and suppressed parasitaemia. Normoglycaemic control was maintained in infected animals through insulin suppression and increasing glucagon secretion, in both acute and chronic studies. Asiatic acid administration curtailed lactate concentration towards normal.Conclusion: Per oral post-infection asiatic acid administration preserved drinking and eating habits, inhibited sickness behaviour while suppressing parasitaemia. Reciprocal relationship between insulin and glucagon concentrations was maintained influencing glucose homeostasis positively and inhibition of hyperlactaemia in malaria.Keywords: Asiatic acid, malaria, Plasmodium berghei, glucose homeostasis, anti disease, anti-parasiti