ABSTRACT
Light to moderate alcohol consumption is associated with improved cardiovascular and brain health. As such, some guidelines for health and wellness advocate drinking one or two alcoholic beverages each day. Conversely, it is widelyaccepted that large amounts of alcohol are detrimental to our health. Alcohol affects many organs of the body including the nervous system. The present study aimed at evaluating the hormetics effect of chronic alcohol consumption on the cognitive, behavioral and brain antioxidant system on adult Wistar Rats.Thirty-two(32) adult Wistar rats of both sexes were divided into 4 experimental groups with 8 animals of both sexes (house separately) in each group: Group1 served as control and was administered distilled water, while Group2 was administered with 0.12g/kg of ethanol, Group3 was administered with 0.16g/kg of ethanol and group4 was administered with 0.24g/kg of ethanol respectively for eleven(11) weeks orally. Cognition was assessed using Morris Water Maze and behavioral activities was assessed using elevatedplus Maze and resident intruder Test before, during and after administration.After administration, the rats were anesthetized lightly with ketamine injection(75mg/kg IP), the brain was removed and part was homogenized in phosphate buffer solution(PBS) for the estimation of Glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), glutathione and malondaldehyde(MDA) and part was fixed in Bouin’s fluid for histological studies. One-way analysis of variance, Repeated measure analysis of variance and Friedman test was used to compare the mean value and p<0.05.The result indicated that there was no significant alternation of learning and memory in control group of male and female rats while in the administered, consistent significant improved learning and memory was observed in dose dependent (Group 2: 37.61±7.34sec,15.26±5.57sec, 12.74±3.44sec; Group 3: 28.72±5.52sec, 12.20±4.31sec, 7.87±2.51sec and Group 4: 26.64±9.64sec, 23.57±1.84sec,
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8.90±3.05sec before, at 5th week and 10th week of administration respectively) over time in male rats while consistent significant improved learning and memory was observed in Group 2(17.47±3.06sec, 7.55±3.90sec, 5.61±2.63sec) and Group 3 (31.30±6.83sec, 10.77±4.31sec) before, at 5th week and 10th week of administration respectively. No significant difference was observed in anxiety like behavior, aggression and brain antioxidant system. Loss of neural processes was observed in Group 4 female.In conclusion, with respect to the present result, daily oral consumption of lose dose of alcohol improve learning and memory in male and female Wistar rats andcould be of health benefit which is in line with mitohormesis concept thereby resulting longevity and could use to delay memory loss associated with aging diseases.
TABLE OF CONTENTS
Cover page ……………………………………………………………………………… i Fly Page …………………………………………………………………………………. ii Title page ………………………………………………………………………………….. iii Declaration page …………………………………………………………………………. iv Certification page ………………………………………………………………………… v Dedication ………………………………………………………………………………… vi Acknowledgements ………………………………………………………………………. vii Abstract …………………………………………………………………………………… viii 1.0 INTRODUCTION………………………………………………………………. 1 1.1 Background of the study ………………………………………………………. 1
1.2 Statement of the Problem……………………………………………………… 5
1.3 Justification of the Study of the Study………………………………………… 6
1.4 Aim and Objectives of the Study ……………………………………………… 7 14.1 Aim of the Study………………………………………………………………… 7
1.4.2 Objectives of the Study…………………………………………………………. 7
1.5 Research Hypothesis ……………………………………………………………. 7
2.0 LITERATURE REVIEW……………………………………………………… 8 2.1 Alcohol Absorption……………………………………………………………… 8 2.2 Alcohol Distribution……………………………………………………………. 9 2.3 Alcohol Metabolism……………………………………………………………… 10 2.4 Alcohol Elimination……………………………………………………………… 12 2.5 Anatomy of the Cerebrum……………………………………………………… 15
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2.5.1 Anatomy Frontal Lobe…………………………………………………………. 18 2.5.1.1 Functional regions of frontal lobe …………………………………………. 19 2.5.1.1.1 Primary motor cortex (M1, Brodmann area 4)…………………………… 19 2.5.1.1.2 Premotor Cortex (BA6)………………………………………………………. 19 2.5.1.1.3 Frontal eye fields (BA8)………………………………………………………. 20 2.5.1.1 4 Dorsolateral prefrontal cortices (BAs 45-49)………………………………. 20 2.5.1.1.5 Cingulate cortex/supplementary motor area (BAs 24, 32)………………. 21 2.5.2 Histology of the cerebral cortex………………………………………………. 23 2.5.2.1 Principal (Projection) neurons …………………………………………………. 24 2.5.2.1.1 Pyramidal neurons……………………………………………………………. 24 .2.5.2.1.2 Fusiform, spindle neurons …………………………………………………… 25 2.5.2.2 Interneurons……………………………………………………………………. 25 2.5.2.2.1 Stellate or granule neurons …………………………………………………. 25 2.5.2.2.2 Horizontal Cells of Cajal……………………………………………………. 25 2.5.2.2.3 Cells of Martinotti…………………………………………………………… 26 2.5.3 Layers …………………………………………………………………………… 27 2.5.3.1 Layer I (Molecular, Plexiform)………………………………………………… 27 2.5.3.2 Layer II (External Granular)…………………………………………………… 27 2.5.3.3 Layer III (External Pyramidal)………………………………………………… 29 2.5.3.4 Layer IV (Internal Granular)…………………………………………………… 29 2.5.3.5 Layer V (Internal Pyramidal)…………………………………………………. 29 2.5.3.6 Layer VI (Multiform)…………………………………………………………… 30 2.6 Effect on Alcohol on Body and Organ Weight………………………………… 32
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2.7 Working Memory …………………………………………………………………34 2.7.1 Alcohol and Working Memory…………………………………………………. 37 2.8 Alcohol and Reactive Oxygen Species (ROS)…………………………………… 38 3.0 MATERIALS AND METHOD…………………………………………………. 44
3.1 Experimental Animals…………………………………………………………… 44
3.1.1 Animal Feed……………………………………………………………………… 44 3.2 Drug Procurement……………………………………………………………… 44
3.3.1 Set Up of Neurobehavioral Studies……………………………………………. 45
3.4 Other Materials…………………………………………………………………… 45 3.5 Experimental Design……………………………………………………………… 45 3.5.1 Body weight assessments………………………………………………………… 45 3.5.2 Neurobehavioral studies………………………………………………………… 46 3.5.2.1 Morris water maze……………………………………………………………… 46 3.5.2.1.1 Setting up the Morris water maze…………………………………………… 46
3.3.1.1.1 Training and testing for the water maze…………………………………… 48
3.5.2.2 Elevated Plus Maze……………………………………………………………. 48
3.5.2.2.1 Setting up and testing for the Elevated plus maze………………………… 48
3.5.2.3 Resident intruder test…………………………………………………………. 49
3.5.2.2.2 Set up and testing for resident intruder test………………………………. 49
3.6 Animal sacrifice…………………………………………………………………. 51 3.7 Biochemical assay………………………………………………………………… 51 3.7.1 Malondialdehyde assay…………………………………………………………. 51
3.7.2 Superoxide dismutase activity assay…………………………………………… 52
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3.7.3 Catalase activity assay…………………………………………………………. 52
3.7.4 Glutathione activity assay……………………………………………………… 52 3.8 Histological Studies……………………………………………………………… 52 3.9 Data Analysis……………………………………………………………………… 53 3.9.1 Body weight analysis……………………………………………………………. 53 3.9.2 Morris water maze test score analysis…………………………………………. 54 3.9.3 Elevated Plus Maze Test Score Analysis………………………………………. 54 3.9.4 Resident intruder Test analysis………………………………………………… 55 3.9.5 Biochemical assay analysis……………………………………………………… 56 4.0 RESULTS………………………………………………………………………… 58 4.1 Physical observation……………………………………………………………… 58 4.2 Body weight assessments………………………………………………………… 58 4.3 Weight gain and brain body weight ratio……………………………………… 61 4.4 Morris Water Maze test scores…………………………………………………. 64 4.5 Elevated plus maze test scores…………………………………………………… 68
4.6 Resident intruder test scores……………………………………………………. 71
4.7 Biochemical studies……………………………………………………………… 74 4.8 Histological studies……………………………………………………………… 77 5.0 DISCUSSION……………………………………………………………………. 94 5.1 Physical observation……………………………………………………………. 94 5.2 Body weight assessments ………………………………………………………… 96 5.3 Cognitive studies………………………………………………………………… 98 5.5 Aggressive related behavioral studies…………………………………………… 102
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5.7 Histological Studies……………………………………………………………… 104
6.0 CONCLUSION………………………………………………………………… 106
6.1 Recommendation………………………………………………………………. 106 6.2 Contribution to knowledge……………………………………………………. 107 REFERENCES……………………………………………………………………………
CHAPTER ONE
1.0 INTRODUCTION 1.1 Background of the study
Alcohol is any chemical organic compound in which the hydroxylfunctional group (–OH) is bound to a saturatedcarbon. The term alcohol originally referred to the primary alcohol ethanol (ethyl alcohol), the predominant alcohol in alcoholic beverages. Ethyl alcohol, or ethanol, is an intoxicating ingredient found in beer, wine, and liquor. Alcohol is produce by the fermentation of yeast, sugars, and starches. It is a central nervous system depressant that is rapidly absorbed from the stomach and small intestine into the bloodstream. A standard drink equals 0.6 ounces of pure ethanol, or 12 ounces of beer; 8 ounces of malt liquor; 5 ounces of wine; or 1.5 ounces (a “shot”) of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey) (NIAAA, 2010). Alcohol affects many organs of the body including the nervous system (Adebisi, 2006) and is thought to cause harm partly because of direct damage to DNA caused by its metabolites (Brooks, 1997).
Alcohol affects brain chemistry by altering levels of neurotransmitters. Neurotransmitters are chemical messengers that transmit the signals throughout the body that control thought processes, behavior and emotion. Neurotransmitters are either excitatory, meaning that they stimulate brain electrical activity, or inhibitory, meaning that they decrease brain electrical activity. Alcohol increases the effects of the inhibitory neurotransmitter GABA in the brain. GABA causes the sluggish movements and slurred speech that often occur in alcoholics. At the same time, alcohol inhibits the excitatory neurotransmitter glutamate. Suppressing this stimulant results in a similar type of physiological slowdown. In addition to increasing the GABA and decreasing the glutamate in the brain, alcohol increases the amount of the chemical dopamine in
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the brain’s reward center, which creates the feeling of pleasure that occurs when someone takes a drink (Klintsovaet al., 2002) Alcoholism can affect the brain and behavior in a variety of ways, and multiple factors can influence these effects. A person’s susceptibility to alcoholism-related brain damage may be associated with his or her age, gender, drinking history, and nutrition, as well as with the vulnerability of specific brain regions (Ammendolaet al., 2000).
Ethanol’s toxicity is largely caused by its primary metabolite, acetaldehyde (systematically ethanal) (Fowkes, 1996) and secondary metabolite, acetic acid (Maxwellet al., 2010). Many primary alcohols are metabolized into aldehydes then to carboxylic acids whose toxicities are similar to acetaldehyde and acetic acid. Metabolite toxicity is reduced in rats fed N-acetylcysteine (Ozaraset al., 2003) and thiamine.
The frontal lobe, located at the front of the brain, is one of the four major lobes of the cerebral cortex in the mammalian brain. The frontal lobe is located at the front of each cerebral hemisphere and positioned in front of the parietal lobe and above and in front of the temporal lobe. It is separated from the parietal lobe by a space between tissues called the central sulcus, and from the temporal lobe by a deep fold called the lateral sulcus also called the Sylvian fissure. The precentral gyrus, forming the posterior border of the frontal lobe, contains the primary motor cortex, which controls voluntary movements of specific body parts (Coffeyet al., 1992)
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The frontal lobe contains most of the dopamine-sensitive neurons in the cerebral cortex. The dopamine system is associated with reward, attention, short-term memory tasks, planning, and motivation. Dopamine tends to limit and select sensory information arriving from the thalamus to the forebrain. A report from the National Institute of Mental Health says a gene variant that reduces dopamine activity in the prefrontal cortex is related to poorer performance and inefficient functioning of that brain region during working memory tasks, and to a slightly increased risk for schizophrenia (NIH/NIMH, 2001) The frontal lobe plays a large role in voluntary movement. It houses the primary motor cortex, which regulates things like walking or punching (Kimberg and Farah, 1993).The function of the frontal lobe involves the ability to project future consequences resulting from current actions, the choice between good and bad actions (or better and best), the override and suppression of socially unacceptable responses, and the determination of similarities and differences between things or events (Kimberg and Farah, 1993).
The frontal lobe also plays an important part in retaining longer-termmemories, which are not task-based. These are often memories associated with emotions derived from input from the brain’s limbic system. The frontal lobe modifies those emotions to generally fit socially acceptable norms (Kimberg and Farah, 1993).
Neuropathological studies performed on the brains of deceased patients have revealed decreased neuron density in the frontal cortex of alcoholics (Harper and Matsumoto, 2005). Harper
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(1998)established that 15–23% of cortical neurons are selectively lost from the frontal association cortex following chronic alcohol consumption.
The frontal lobes are connected with the other lobes of the brain, and through multiple interconnections, they receive and send fibers to numerous subcortical structures as well (Fuster, 2006). The anterior region of the frontal lobes (prefrontal cortex) plays a kind of executive regulatory role within the brain (Goldberg, 2001). Executive functions (which depend upon many of our cognitive abilities, such as attention, perception, memory, and language) are defined differently by different theorists and researchers. Most agree, however, that executive functions are human qualities, including self-awareness, that allow us to be independent individuals with purpose and foresight about what we will do and how we behave. For example, executive abilities include judgment, problem solving, decision-making, planning, and social conduct, and they allow us to monitor and change behavior flexibly and in accord with internal goals and contextual demands (Oscar-Berman and Marinković, 2007).
An alcoholic who is a highly skilled professional, for example, an engineer or professor, may be perfectly able to perform regular duties such as temporal and spatial orientation, naming things, and calculations. However, this highly skilled person may be frontally impaired and unable to change or control their use of alcohol or drugs, even knowing that this behavior was and is harmful, or make important decisions in urgent situations. Imagine this highly skilled alcoholic subject driving on a road and a soccer ball unexpectedly crosses in front of his or her car, likely followed by a child. Most of us would bring together all faculties needed to evaluate the
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situation, the possible consequences, and quickly take action, even if you hurt yourself (Nakamura-Palacios et al., 2014). Clearly, alcohol affects the brain. Some of these impairments (Difficulty walking blurred vision, slurred speech, slowed reaction times, impaired memory) are detectable after only one or two drinks and quickly resolve when drinking stops (White, 2003). On the other hand, a person who drinks heavily over a long period of time may have brain deficits that persist well after he or she achieves sobriety. Exactly how alcohol affects the brain and the likelihood of reversing the impact of heavy drinking on the brain remain hot topics in alcohol research today. Most of us have witnessed the outward signs of heavy drinking: the stumbling walk, slurred words and memory lapses. People who have been drinking have trouble with their balance, judgment and coordination. They react slowly to stimuli, which is why drinking before driving is so dangerous. All of these physical signs occur because of the way alcohol affects the brain and central nervous system.
1.2 Statement of the Problem
Alcohol and its use is so deeply engrained into our social and cultural environment that it may appear counter-intuitive to have to describe it. However, this over familiarity with alcohol poses in itself an enormous challenge for the promotion of healthier life-styles. The chronic consumption of alcohol is common and the effect is costly. Excessive alcohol use decrease quality of life, academic performance, workplace productivity, and military preparedness; increase crime and criminal justice expenses; increase motor vehicle crashes and fatalities.
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The brain, like most body organs, is vulnerable to injury from alcohol consumption, frontal lobe of the cerebrum being the most vulnerable part and because of its function being the main controlling center for executive function of the brain and other associated function (influences emotion, motor function, problem solving, memory, judgment, impulse control, social and sexual control and language), any damage to this part of the brain will affect the well-being of an individual. These lobes located in the front of the whole brain control our behavior and are responsible for the acts that separate the homo ‘thinker’ sapiens from the rest of the animal kingdom. The frontal lobes control and inhibit our primal impulses; this inhibition of such impulses prevents us from taking dangerous risks, or behaving in a deviant way, and facilitates our living as a community (Nakamura-Palacios et al., 2014) 1.3 Justification of the Study of the Study Alcohol is part of our society as it is used for social and religious ceremonies. But drinking too much on a single occasion or over time can have serious consequences for our health.
Alcoholism-related cortical changes have been documented throughout the brain, many studies consistently have found the frontal lobes to be more vulnerable to alcohol-related brain damage than other cerebral regions (Dirksen et al., 2006).However, Elias et al., (1999) reported that moderate alcohol intake may be beneficial to cognitive activities and cardiovascular diseases from epidemiology research but there is paucity of literatures to backup this report from animal models.
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Hence, this study will significantly contribute to the literature on the effect of chronic moderate alcohol intake in animal models. 1.4 Aim and Objectives of the Study 14.1 Aim of the Study This study was aim at evaluating the effect of chronic alcohol consumption on the frontal lobe of the cerebrum of adult Wistar rats
1.4.2 Objectives of the Study The objectives of the study were to evaluate the frontal lobe following of chronic alcohol administration;
i. on histo-architecture of frontal lobe.
ii. on cognitive activities, aggression and anxiety using neuro-behavioural tests.
iii. on activities of superoxide dismutase and catalase, glutathione and malnoaldehyde level.
1.5Research Hypothesis
Chronic oral administrationof low dose of alcohol haseffect on the frontal lobe of the Wistar rats.
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