CHAPTER ONE
INTRODUCTION
The quest for the discovery of new anti-inflammatory and antioxidant drugs was born out of the increasing side effects associated with the use of synthetic drugs. Non-steroidal anti-inflammatory drugs (NSAIDS) which are the most commonly prescribed drugs in clinical settings for the treatment of inflammation related diseases and / disorders are associated with adverse effects especially on the cardiovascular system (CVS) and gastrointestinal (GI) tract (Hasnain et al., 2016). The corticosteroids have severe side effects, such as constipation, sedation, respiratory depression, hallucinations and immunosuppression which may be annoying or dangerous for the patient (Susunaga-Notario et al., 2014; Oray et al., 2016). In addition, available synthetic antioxidants like butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT) are currently restricted in many countries due to their carcinogenic and other toxic effects (Damgaard et al., 2014; Chipiti et al., 2015). In order to circumvent these adverse effects, there has been an upsurge of interest in the therapeutic potential of medicinal plants as anti-inflammatory and antioxidative agent in reducing free radical induced tissue injury with less undesirable effects (Ouedraogo et al., 2011; Ogugua et al., 2013). Many plants contain natural products such as flavonoids, alkaloids, tannins, terpenoids, phenols and saponins which are promising agents in the treatment of numerous diseases including inflammation (Rani et al., 2014). Studies have shown that some of these secondary metabolites not only inhibit inflammation but are also effective in neutralizing reactive species involved in the pathogenesis of oxidative stress related disorders (Bellik et al., 2013).
Brenaniabrieyi is aflowering plant in the Rubiaceaefamily. It is used in traditional medicine for treatment of fever, pain, swelling, and endocrine disorders (Nde et al., 2007).  Most of the plants used by traditional herbalists in treatment of ailments are used without scientific investigation. In view of all the various trado-medical applications of Brenaniabrieyi and the numerous side effects associated with the use of synthetic inflammatory drugs, methodical investigation  of the anti-inflammatory and antioxidant potential of Brenaniabrieyicould help in the search for newer, cheaper and safer alternative drug for the treatment and management of several ailments, especially inflammatory diseases. This work was therefore aimed at evaluating the anti-inflammatory and antioxidant activities of the methanol and chloroform extracts of the root bark of B. brieyi using animal models.
1.1 Overview of inflammation
Inflammation is a complex protective response of vascular tissues to invasion by harmful stimuli (Anosike et al., 2012a; Enechi and Nwodo, 2015). The primary functions of inflammation are to rapidly destroy or isolate the injurious agent, remove damaged tissue, and then restore tissue homeostasis (Markiewski and Lambris, 2007; Ashley et al., 2012; Benly 2015). The factors that can stimulate inflammation include physical agents, irritants, chemicals, inappropriate immunological responses, damaged tissues and microbial products (Nile and Park, 2013; Hemalata and Shiva, 2015). There are generally five cardinal signs of inflammation namely: redness, swelling, heat, pain and loss of function. The redness is caused by increase of blood volume in the inflamed part; swelling is as a result of increased blood flow and presence of other substances which exude from the blood vessels into the surrounding tissues, heat is due to increased flow of blood through the inflamed region, pain is often attributed to increased pressure on nerve endings which is induced by certain chemical mediators of inflammation from platelet, neutrophils, mast cells and monocytes/macrophages and loss of function may result from pain that inhibits mobility or from severe swelling that prevents movement in the area. (Markiewski and Lambris, 2007; Ekwueme et al., 2011; Hemalata and Shiva, 2015).
Paradoxically, inflammatory responses which help in adaptive response to tissue malfunction or homeostatic imbalance can be very harmful to the host if not tightly controlled or regulated and also when provoked in excess (Italiani and Boraschi, 2014). The complex events and mediators involved in the inflammatory reactions can induce, maintain or aggravate many diseases (Anosike et al., 2012a) such as rheumatic arthritis, lung fibrosis, cancer (Ekwueme etal., 2015), diabetes, ageing, obesity, cardiovascular, intestinal, renal and neurological disorders (Lalrinzuali et al., 2016). Inflammation also causes life threatening events which includes destruction of normal tissues, swelling, and delay in regenerating muscle fibre upon myoinjury (Liu et al., 2015).
Inflammation is controlled by a balance of pro-inflammatory and anti-inflammatory signals, resulting in the development of an immune response followed by temporarily released pre-resolution factors that lead to inflammation switching off, and injured tissues returning to normal physiology (Rajakariar et al., 2008). If unresolved, inflammatory responses cause injury to host tissues, which can lead to the development of a wide variety of immune-mediated pathologies. In the healthy individual, inflammation is self-limiting, and resolution is controlled by the release of anti-inflammatory mediators and cytokines, such as interleukin-10 (IL-10) (Rosser and Mauri, 2015).
1.2 Phases of inflammation
Inflammatory responses can be categorized into two main phases namely: Acute and chronic phases.
a. Acute phase
Acute phase is the first line of defense against injury which begins within seconds to minutes or few days following the injury of tissue (Ahmed, 2011). It starts with increased movement of plasma and leukocytes from the blood into the injured tissues. The main events in acute phase are vascular in origin and remarkably consistent for a wide range of stimuli. The process of acute inflammation is initiated by cells already present in the tissues and is characterized by marked vascular changes, including vasodilatation and increased capillary permeability, oedema and neutrophils infiltration which are induced by the actions of the various inflammatory mediators (Anosike et al., 2012b; Braga et al., 2015). Nevertheless, the response exhibits considerable differences that depend, first, on factors related to the injury or infection and, second, on the condition of the host and nature of the tissue involved (Silva, 2015). Proper resolution of acute inflammation leads to recovery of normal function and homeostasis (Oishi and Manabe, 2015).
b. Chronic phase
Inflammation may pass to chronic phase if conditions causing acute inflammation is not properly resolved. Chronic phase is a prolonged condition in which inflammation, tissue injury and attempt to repair coexist (Oishi and Manabe, 2015). It occurs when the immune system is persistently activated as a result of prolonged exposure to a toxic agent, persistent injury or infection and autoimmune diseases. In addition, some pathogens can directly provoke chronic inflammation without passing through the acute phase. Chronic phase is often characterized by a deficiency in the number and function of inflammatory suppressor cells in circulation and at the site of inflammation (Rosser and Mauri, 2015). The beginning of chronic phase is often characterized by the replacement of neutrophils with macrophages and other immune cells, such as T cells (Ashley et al., 2012). These cells provide a powerful defensive mechanism in the body, but the mediators they release are injurious to the organism’s own tissues, as well as invading agents. This is why chronic inflammation is almost always accompanied by tissue destruction (Silva, 2015). Chronic phase is also associated with blood vessels proliferation, and fibrosis. There are several possible mechanisms of chronic inflammation: (i) persistent production of reactive molecules by infiltrating leukocytes designed to kill pathogens, which eventually damages the structural and cellular elements of tissues (Bala and Haldar, 2013); (ii) damaged nonimmune cells and activated immune cells lead to the production of cytokines that amplify or modulate the inflammatory response and alter the phenotypes of nearby cells, often to the detriment of normal tissue function (Franceschi and Campisi, 2014). There is also secretion of immunosuppressive cytokines involved in wound healing, remodeling and repair (Gensel and Zhang, 2015).
