ABSTRACT
Ischaemic brain injuries, that results from stroke, are common and often lead to permanent residual disabilities. This work investigates the role Piracetam, a nootrophic drug, played in modulation of induced brain injury to key areas of the brain; cerebrum, cerebellum and hippocampus of adult Wistar rats. Drugs like Vitamin C, Vitamin E and corticosteroids have been known to improve damage resulting from ischaemic damage to the brain. Piracetam, like wise has been known to improve higher brain functions such as memory and mental alertness. The effect of paracetam was investigated on twenty wistar rats that were divided into five groups of four animals each. Ischaemic brain injury was then induced by transient bilateral occlusion of the carotid arteries. Motor function and memory was assessed and comparison made between those animals that did not receive any drugs and those that received Piracetam and or vitamin E. Serum and brain malonylaldehyde (MDA) levels, histological assessment of cerebrum, cerebellum and hippocampal brain were studied in animals in the various groups. Results show that the percentage and grade of excitability score, forepaw grip time and transfer latency period in an elevated plus maze was higher for those animals that received vitamin E or a combination of vitamin E and Piracetam when compared with those that received Piracetam only. The differences were however not statistically significant. Serum malonylaldehyde was found to be significantly higher in those animals that did not receive any drugs following induction of ischaemia when compared with those that received either Piracetam, vitamin E or a combination of the two drugs. Furthermore serum malonylaldehyde levels were significantly higher in those groups that received vitamin E when compared to those that received Piracetam only. Brain tissue malonylaldehyde levels were found to be higher in those animals that received Piracetam only when compared with the group that received a combination of the two drugs. When vitamin E alone was administered, malonylaldehyde levels in the brain were higher when compared to the group that received Piracetam only. Photomicrographs of the cerebral cortex, cerebellum and hippocampus showed marked evidence of neurodegeneration in the untreated group compared to those groups that received drug treatment. Among the groups treated, neuronal cell ischaemic changes were more evident in the group treated with Piracetam alone when compared with the groups treated with Piracetam and or vitamin E.
TABLE OF CONTENTS
Title page – – – – – – – – – i Declaration – – – – – – – – – ii Certification – – – – – – – – – iii Dedication – – – – – – – – – iv Acknowledgement – – – – – – – – v Abstract – – – – – – – – – vi Table of contents – – – – – – – – vii List of tables – – – – – – – – – ix List of figures – – – – – – – – – x List of plates – – – – – – – – – xi List of acronyms – – – – – – – – xiv Chapter One – Introduction – – – – – – – – 1 1.1 Justification- – – – – – – – 3 1.2 Aim and Objective – – – – – – 5 1.3 Hypothesis – – – – – – 5 Chapter Two – Literature Review – – – – – – – 6 2.1 Piracetam – – – – – – – – 6 2.1.1 Uses of Piracetam – – – 7 2.1.2 Mechanism of action of Piracetam – 9 2.1.3 Toxicity of Piracetam – – – 11 2.2 Ischaemia – – – – – – – – 12 2.3 Brain – – – – – – – – 19 2.4 Vertebrate Brain – – – – – – 19 2.5 Human Brain – – – – – – – 20
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2.6 Memory – – – – – – – 24 2.7 Stroke – – – – – – – 25 2.7.1 Pathophysiology of Stroke – – 26 2.8 Wistar Rat Brain – – – – – – 29 Chapter Three – Materials and Methods – – – – – 36 3.1 Materials – – – – – – – 36 3.1.1 Instruments – – – – 36 3.1.2 Chemicals and Drugs – – – 36 3.1.3 Animals – – – – 36 3.2 Methods – – – – – – – 36 3.2.1 Design of the Study – – – 36 3.2.2 Experimental Induction of Ischaemia – 37 3.2.3 Apparatus for Physiological Test – 38 3.2.4 Assessment of Lipid Peroxidation – 38 Chapter Four – Results – – – – – – – 40 Chapter Five – Discussion – – – – – – – 96 5.1 Discussion – – – – – – – 96 Chapter Six – Conclusion and Recommendation – – – – – 100 6.1 Conclusion – – – – – – – 100 6.2 Recommendation – – – – – – 101 References – – – – – – – – – 102 Appendices – – – – – – – – – 105
CHAPTER ONE
INTRODUCTION ischaemia is literally translated from Greek meaning a restriction in blood supply, with resultant damage or dysfunction of tissue (Lionel, 1990). This is different from hypoxia, a general term denoting oxygen shortage which usually results from lack of oxygen in the air. ischaemia can be defined as an absolute or relative shortage of the blood supply to an organ (Klabunde, 2004). ischaemia does not occur without hypoxia, while the reverse is not the case. This implies that in ischaemia, there is a shortage of oxygen as well as glucose and other blood-borne nutrients and other materials. This mismatch in availability of oxygen and nutrients, in comparison to their need in the organisms metabolism results in more severe damage than that caused by hypoxia, because of the potential for toxic metabolic wastes to build up in the tissues. ischaemia commonly results from inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it (Hossmann, 1998). It is through such mechanism that stroke commonly occurs.
Neuronal cell damage is generally a potentially serious problem for two reasons: First, nerve cells do not regenerate: therefore neuronal cells with the exception of neural stem cells and a few other types of neurons, do not undergo mitotic cell division(Ruggiero et al., 2012 ). In most cases, neurons are generated by special types of stem cells. Astrocytes, a type of glial cell, have also been observed to turn into neurons by virtue of the stem cell characteristic pluripotency (Addis et al., 2011). In humans, neurogenesis largely ceases during adulthood. Only for two brain areas, the hippocampus and olfactory
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bulb, is there strong evidence for generation of substantial numbers of new neurons (Gould et al., 1999). Secondly, brain function directly controls the activity in other parts of the body, thus, neuronal cell damage in a small region of the brain can significantly hamper activity and may even threaten life (Schmued et al., 2000). Severe or prolonged brain ischaemia will result in unconsciousness, brain damage or death, mediated by the ISCHAEMIC cascade. Multiple cerebral ISCHAEMIC events may lead to subcortical ISCHAEMIC depression, also known as vascular depression. Late onset depression is increasingly seen as a distinct sub-type of depression, and can be detected with an MRI (Baldwin, 2004). ischaemia leads to alterations in brain metabolism, reduction in metabolic rates, and energy crisis.
There are two types of ischaemia: focal ischaemia, which is confined to a specific region of the brain; and global ischaemia, which encompasses wide areas of brain tissue. Their main symptoms involve impairments in vision, body movement, and speaking. The causes of brain ischaemia vary from sickle cell anemia to congenital heart defects. Restoration of blood flow after a period of ischaemia can actually be more damaging than the ischaemia. Moreover, reintroduction of oxygen causes a greater production of damaging free radicals, resulting in reperfusion injury. With reperfusion injury, necrosis can be greatly accelerated (Jie et al., 2007). Piracetam (2-oxo-1-pyrrolidine acetamide), is the first of the nootrophic drugs. This class of drugs affects mental function.
Piracetam was first synthesized in 1964 by the Belgian pharmaceutical company UCB (Shorvon, 2004). It has been shown to improve higher functions of the brain like learning
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and memory, but, does not cause sedation, nor stimulate the central nervous system. Relatively few side effects are known. In the words of C.E. Giurgea, UCB‟s principal Piracetam researcher, nootropic drugs like Piracetam should be able to: Enhance learning and memory. Enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. hypoxia). Protect the brain against various physical or chemical injuries (e.g. barbiturates). Increase the efficacy of the tonic cortical/subcortical control mechanisms. Lack the usual pharmacology of other psychotropic drugs, Possess very few side effects and have extremely low toxicity (Gamzu et al., 1989).
However its mechanism of action is still generally unclear (Winblad, 2005). Complications of chronic diseases such as hypertension and diabetes, cardiovascular diseases and traumatic head injuries can commonly result to stroke which can be easily fatal. This study is designed to investigate outcome of ISCHAEMIC damage to the brain when Piracetam alone and in combination with a known anti oxidant, vitamin E is administered immediately following the induction of brain ischaemia. 1.1 JUSTIFICATION According to the World Health Organization, 15 million people suffer stroke worldwide each year. Of these, 5 million die and another 5 million are permanently disabled.
Stroke is the third most common cause of death in the United States (US). More than 140,000 people die each year from stroke in the United States. Stroke also results in substantial health-care expenditures; the mean lifetime cost resulting from an
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ISCHAEMIC stroke is estimated at $140,000 per patient in the US (Rosamond et al., 2007). Europe averages approximately 650,000 stroke deaths each year (Redon et al., 2011). Comprehensive stroke surveillance data for Africa are lacking, the available data show that age-standardized mortality, case fatality, and prevalence of disabling stroke in Africa are similar to or higher than those measures in most high-income regions (Mensah, 2007). The current prevalence of stroke in Nigeria is 1.14 per 1000 while the 30-day case fatality rate is as high as 40%. Management of the disease is largely conservative (Wahab, 2008). Despite this heavy burden stroke has placed on society, the search for a „„magic bullet‟‟ for the treatment of stroke or traumatic brain injury (TBI) has failed thus far. This is partly because the pathophysiology of ISCHAEMIC brain injury and TBI involves a number of mechanisms leading to neuronal injury, including excitotoxicity, free radical damage, inflammation, necrosis, and apoptosis (Sayeed & Stein, 2009). The common pathway for all these factors in causing brain ischaemia is loss of cell membrane integrity. A popular hypodissertation concerning Piracetam is it restores cell membrane fluidity following an insult (Muller, 1999; Winblad, 2005). This is the basis for which it is used in a wide range of diseases affecting many different organ systems.
This investigation is therefore pertinent to define the role Piracetam can play in modulating brain injury in stroke especially in developing countries like Nigeria.
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1.2 AIM AND OBJECTIVES Aim The aim of this study is to determine the effect of Piracetam on ISCHAEMIC brain injury in Wistar rats when used alone and compare with its effect when used in conjunction with vitamin E which is a known anti oxidant. Objectives
1. To assess the effect of Piracetam and or vitamin E on malonylaldehyde in blood and brain tissue of ISCHAEMIC Wistar rats
2. To study the effect of transient ischaemia on the cytoachitecture of cerebrum, cerebellum and hippocampus of Wistar rats
3. To determine the effect of Piracetam and or vitamin E on the cytoachitecture of cerebrum, cerebellum and hippocampus of ISCHAEMIC Wistar rats
4. To observe the effect of Piracetam and or vitamin E on memory and motor activity of ISCHAEMIC Wistar rats
1.3 HYPOTHESIS ISCHAEMIC brain injury can be modulated by Piracetam and or Vitamin E. Null Hypotheses ISCHAEMIC brain injury is not modulated by Piracetam and or vitamin E.
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