Nitric oxide (NO) is heavily involved in biochemical signaling and regulation in humans. This multi-functional molecule is synthesized by nitric oxide synthases (NOSs) from L-arginine (Figure 1)4. Three NOS isoforms exist in humans: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Of the three, the most relevant to this paper is nNOS, which regulates biochemical networks in the nervous system and skeletal muscles. The other two, eNOS and iNOS, serve as signaling and regulatory molecules in the circulatory system and immune system, respectively. However, in instances of NO overproduction, the body can be severely harmed. One example of detrimental NO overproduction exists in in the aftermath of traumatic brain injury. …show more content…
(2010) and Poulos & Li (2013), is N1-[(3’S, 4’S)-4’-((6”-amino-4”-methylpyridin-2”-yl)methyl-pyrroldin-3’-yl]-N2-(3’-flurophenethyl) ethane-1,2-diamine tetrahydrochloride, or (3’S, 4’S) (Figure 2). Put simply, this compound is composed of an aminopyridine head, pyrroldine bridge group, and tail. The primary function of the aminopyridine head is to mimic the guanidinium group of L-arginine and bind to Glu592 in the nNOS isoform. In addition, the fluorophenyl group extends out of the active site and further stabilized by amino acids unique to nNOS structure. This action competitively inhibits nNOS function, significantly decreasing NO …show more content…
It has generally been found that arginine-based inhibitors, such as (3’S, 4’S), have the most associated disadvantages when compared to other types of inhibitors. These disadvantages include a lower specificity to a specific NOS isoform, high basicity, polarity, and hydrogen-bonding potential. The latter three factors decrease the arginine-based inhibitor’s ability to function in specific parts of the body, such as in the brain3. Currently, the most promising inhibitor types are a simple aminopyridine structures. These structures are similar to arginine-based inhibitors in that they amino-acid based; however, these molecules have been modified with groups that increase selectivity and binding affinity to a specific NOS isoform, and hindering groups have been removed3. Research has also been performed to investigate inhibitors for other regions of an NOS isoform, including H4B antagonists and calmodulin
When an injury is sustained by the human body, such as a concussion that affects the limbic system, can results in temporary amnesia. However, when the damage to the brain is significant enough, the limbic system found in the forebrain cannot recover. Since the forebrain is injured significantly, the acetylcholine production is decreased; therefore, motor memory, long term memory, and short term memory are affected negatively.
Neurometabolic cascade of concussion can occur with any type of external force to the head. These events can cause the brain to accelerate and decelerate with translational, rotational and/or angular forces. In most cases, the brain will generally correct itself and the majority of patients will fully recover. However, while the brain is still recovering, the reduction in cerebral blood flow may result in cell dysfunction that increases the vulnerability.
It is also unclear if it is the brain injury itself that causes the result and if it is the same for healthy people.
Concussions are minor traumatic brain injuries caused by bumping the head. The action taking place that causes a concussion is when the brain bounces around in the skull causing minor to major bruising. This causes chemical changes in the brain and leaves the damaged areas in the brain vulnerable to permanent damage if injured again. Symptoms involve “impairments of memory and attention, headache, and alteration of mental status, are the result of neuronal dysfunction mostly caused by functional rather than structural abnormalities” ( Signoretti, 2011). According to Signoretti, the symptoms occur because of the trauma causes the neurons to fall out of homeostasis causing a chain reaction of metabolic events such as temporary
The frontal cortex is the repository of the highest order cognitive functions. Being at the front of the head, it is susceptible to damage in frontal collisions, as it endures the highest-force portion of the trauma prior to dissipation (Stein, Alvarez, & McKee, 2015). Repeated concussion of the brain kills neurons, which may be an attempt by the brain to compensate for the injury or heal (Borich, 2013). Regardless, killing off large numbers of neurons is degeneration of the brain, and persistent concussion that kills many neurons impedes core higher order brain functions. Long-term brain damage from concussion has diverse symptoms that include convulsions, seizures, depression, cognitive degradation/impairment, and psychosis (Stein, Alvarez, & McKee, 2015).
This brain injury also includes the “production of harmful chemicals called free radicals, inflammation, impaired transport of molecules within nerve cells, and imbalances of key ions needed for nerve function” (Menon 1). Memory is also effected by a concussion. Short term memory is often “individuals complain that they cannot remember something they just saw, or things that were just said. This is the most common type of memory problem” (French 1). Long term memory impact is viewed as “individuals who suffer a head injury are able to remember things that occurred in the past, but may struggle with things that happened recently” (French 1). When a concussion happens it is mostly common to only be effective to short term memory. Concussions not only potentially bruise your brain but produces harmful chemicals. A concussion causes “injury to the nerves in the scalp or larger nerves in the face and upper neck from the trauma can result in head discomfort” (Zasler 1). Head discomfort includes piercing headaches and lasting head pain. The nervous system is effected in negative ways because at the moment of impact to the brain, the nerve tissues are stretched and teared causing great pain.
In order to understand NO’s neurobiological roles, some of NO’s biochemistry and physiology must be discussed. NO’s radical structure, fleeting half-life, and rapid diffusibility make it an ideal neurotransmitter, albeit an unconventional one. In the peripheral vascular blood supply, acetylcholine or bradykinin act on endothelial cells in the vessels which causes a release of endothelium-derived relaxation factor (EDRF) which has been verified to be NO (Snyder;1992). Acetylcholine or bradykinin causes an increase in the intracellular Ca2+ concentration through the action of inositol triphosphate; the increased intracellular Ca+ binds the calmodulin site in NOS and stimulates the synthesis of NO which rapidly diffuses away from its site of synthesis to the tunica muscularis of blood vessels causing vasodilation (Murray;1993). In this manner, NO is a sort of second neurotransmitter potentiating the effects of acetylcholine or bradykinin on the muscular layer of blood vessels. In this system, NOS is located in the endothelial cells; however, in the cerebral arteries, NOS is located in the nerve plexus themselves in the outer layer of cerebral arteries, and the cell bodies of these neurons lie in the sphenopalatine
Traumatic brain injury in general is characterized by the changes in brain function due to some sort of a biomechanical force induced by either directly or indirectly as a hit or blow to the head (Facts and Prevention, 2015). Mild traumatic brain injury, which will be considered as equivalent term with concussion, was defined by the International Conference on Concussion in Sport as a complex pathophysiological process induced by biomechanical forces (Mccrory et al., 2013). This penetrating head injury will disrupt the normal function of the brain. The cause of sports-related brain injury can be induced by a direct or indirect blow to the head. Injury can also be caused by the force of impulse due to impacts on other parts of the body being
Tosedostat’s inhibitory effects against aminopeptidase can induce amino acid deprivation response in a group of cancer cells, including solid tumour, leukaemia, and myeloma cell lines. It up-regulated several pro-apoptotic factors including CHOP and NOXA, activated NFκB and inhibited mTOR, all of which together led to protein synthesis termination. When applied in combination with other antitumor drugs, tosedostat showed synergistic effects in treating solid and haematological cancer cells. [2]
Brain trauma can cause a build -up of abnormal types of protein called tau, which slowly kills brain cells. Once started, these changes in the brain appear to continue and
Medical and technological advances have led to greater survival rates in individuals suffering from various illness and injury throughout history. This includes individuals who suffer traumatic and nontraumatic brain injuries. Approximately 1.5 million people in the United States sustain a brain injury each year with the survival rate of over 90 percent making brain injury the leading cause for disability in the United States. (Mysiw, Bogner, Corrigan, Fugate, Clinchot, & Kadyan 2006). Cognitive, physical, sensory and behavioral changes are widely noted in individuals in the months and years following a brain injury. However, the psychosocial, psychological and emotional effects of these injuries are less discussed and therefore these aspects can be overlooked when anticipating a course of treatment. Individuals who sustain acquired brain injuries experience significant, lasting impairment in the psychosocial, psychological and emotional aspects of their lives and better understanding of these issues can lead to better treatment and coping skills for these individuals.
Traumatic brain injury (TBI) is a type of injury that is a critical public health and socio-economic problem. TBI is a leading cause of death and disability in both children and adults [5]. The Centers for Disease Control and
As we all know, the human brain is the most insubstantial and vital organ in the human body as it is the command center for every other body part (newscientist.com). Any slight wound to this organ could lead to severe consequences usually encountered at that very moment. It may be an extremely low chance of a major head injury, but it does happen to millions of people annually. One single concussion, provided with the lack of healing, could lead to short-term and long-term memory loss, depression,
Emerging evidence indicates that free radicals are involved in the pathogenesis of several digestive system disorders as well as in the regulation of biological processes such as aging. Previous reports have indicated that opioids induce apoptosis via stimulating an oxidative stress pathway that is associated with the production of superoxide and nitric oxide (NO) [11]. NO, together with reactive oxygen species (ROS), has a pivotal role in the regulation of apoptosis and necrosis in various cells. Hsiao et al. investigated the role of NO and ROS in the morphine-induced apoptosis. They found that the morphine treatment enhanced apoptosis through both NO and ROS pathways [12]. The inducible nitric oxide synthase (iNOS) enzyme is one of the most important enzymes involved in the generation of NO from the amino acid L-arginine.
Nitric oxide (NO) is essential for various functions in the cardiovascular system which include: controlling vascular tone, relaxing vascular smooth muscles, reducing blood pressure, dilating blood vessels, and preventing thrombotic events. Abnormalities in the production or availability of NO can cause hypertension, atherosclerosis and angiogenesis-associated disorders (Zhao et al., 2015).