The Nervous System

1. The Nervous System • The human nervous system can be divided into two parts: the central nervous system (CNS) and the peripheral nervous system (PNS) • http://pennhealth.com/health_info/animationplayer/nerve_conduction.html

2. Central Nervous System Drugs that affect the CNS can: Selectively relieve pain Reduce fever Suppress disordered movement Induce sleep or arousal Reduce appetite Allay the tendency to vomit Be used to treat anxiety, depression, schizophrenia, Parkinson’s Disease, Alzheimer’s Disease, epilepsy, migraine, etc.

3. How do drugs work in the CNS? • “A central underlying concept of neuropharmacology is that drugs that influence behavior and improve the functional status of patients with neurological or psychiatric diseases act by enhancing or blunting the effectiveness of specific combinations of synaptic transmitter actions.”

4. Blood Brain Barrier (BBB) • A physiological mechanism that alters the permeability of brain capillaries, so that some substances, such as certain drugs, are prevented from entering brain tissue, while other substances are allowed to enter freely. • The separation of the brain, which is bathed in a clear cerebrospinal fluid, from the bloodstream. The cells near the capillary beds external to the brain selectively filter the molecules that are allowed to enter the brain, creating a more stable, nearly pathogen-free environment.

8. Diagram of a cerebral capillary enclosed in astrocyte end-feet. Characteristics of the blood-brain barrier are indicated: (1) tight junctions that seal the pathway between the capillary (endothelial) cells; (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier towater-soluble molecules; (3), (4), and (5) represent some of the carriers and ion channels; (6) the 'enzymatic barrier'that removes molecules from the blood; (7) the efflux pumps which extrude fat-soluble molecules that have crossed into the cells

9. Blood-Brain-Barrier • Oxygen, glucose, and white blood cells are molecules that are able to pass through this barrier. Red blood cells cannot.

10. Blood Brain Barrier • The blood-brain barrier (abbreviated BBB) is composed of endothelial cells packed tightly in brain capillaries that more greatly restrict passage of substances from the bloodstream than do endothelial cells in capillaries elsewhere in the body. • Processes from astrocytes surround the epithelial cells of the BBB providing biochemical support to the epithelial cells. • The BBB should not be confused with the blood-cerebrospinal fluid barrier (BCB), a function of the choroid plexus.

13. History of the BBB • The existence of such a barrier was first noticed in experiments by Paul Ehrlich in the late-19th century. Ehrlich was a bacteriologist who was studying staining, used for many studies to make fine structures visible. Some of these dyes, notably the aniline dyes that were then popular, would stain all of the organs of an animal except the brain when injected. At the time, Ehrlich attributed this to the brain simply not picking up as much of the dye.

14. However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich's students) injected the dye into the spinal fluid of the brain directly. • He found that in this case the brain would become dyed, but the rest of the body remained dye-free. This clearly demonstrated the existence of some sort of barrier between the two sections of the body.

15. History of the BBB • At the time, it was thought that the blood vessels themselves were responsible for the barrier, as there was no obvious membrane that could be found. • It was not until the introduction of the scanning electron microscope to the medical research fields in the 1960s that this could be demonstrated. The concept of the blood-brain (then termed hematoencephalic) barrier was proposed by Lina Stern in 1921.

16. What is the purpose of the BBB? • The blood-brain barrier protects the brain from the many chemicals flowing around the body. • For example, many bodily functions are controlled by hormones, which are detected by receptors on the plasma membranes of targeted cells throughout the body. • The secretion of many hormones are controlled by the brain, but these hormones generally do not penetrate the brain from the blood, so in order to control the rate of hormone secretion effectively, there are specialized sites where neurons can "sample" the composition of the circulating blood.

17. At these sites, the blood-brain barrier is 'leaky'; these sites include three important 'circumventricular organs', the subfornical organ, the area postrema and the organum vasculosum of the lamina terminalis (OVLT). • The blood-brain barrier is also an effective way to protect the brain from common infections. Thus infections of the brain are very rare; however, as antibodies are too large to cross the blood-brain barrier, when infections of the brain do occur they can be very serious and difficult to treat.

18. How does the BBB affect the design of therapeutic agents? • Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. • Modalities for drug delivery through the BBB entail disruption of the BBB by osmotic means, biochemically by the use of vasoactive substances such as bradykinin, or even by localized exposure to high intensity focused ultrasound (HIFU). • The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored.

19. The Blood Brain Barrier • http://www.clinicaloptions.com/HIV/Management%20Series/NeuroAIDS/Animation/Blood%20Brain%20Barrier.aspx

20. Introduction to the CNS • http://biosingularity.wordpress.com/2007/05/07/neurons-and-how-they-work-animation • http://www.healthscout.com/animation/68/10/main.html

21. Neurotransmitters found in the CNS

22. It’s a balancing act!! • Current models of CNS diseases often attribute the physiological cause of the disease to an imbalance of neurotransmitters.

23. Acetylcholine • All ACh receptors in the CNS are nicotinergic. The stimulating effect of nicotine is due to the influence of these receptors. • Acetylcholine is transmitted within cholinergic pathways that are concentrated mainly in specific regions of the brainstem and are thought to be involved in cognitive functions, especially memory. Severe damage to these pathways is the probable cause of Alzheimer’s disease.

24. Norepinephrine • Most cell bodies of noradrenergic neurons are in the locus coeruleus, a center in the brain stem. These neurons send their axons to the limbic system (appetite inhibition), the subcortical centers and the cerebral cortex (arousal). • Noradrenaline is classed as a monoamine neurotransmitter and noradrenergic neuronsﾊ are found in the locus coeruleusﾊ, the pons and the reticular formation in the brain. These neurons provide projections to the cortex, hippocampusﾊ, thalamusﾊ and midbrain. The release of noradrenaline tends to increase the level of excitatory activity within the brain, and noradrenergic pathways are thought to be particularly involved in the control of functions such as attention and arousal.

25. Locus ceruleus • The Locus ceruleus, also spelled locus caeruleus or locus coeruleus (Latin for 'the blue spot'), is a nucleus in the brain stem responsible for physiological responses to stress and panic.The locus ceruleus (or "LC") is located within the dorsal wall of the upper pons, under the cerebellum in the caudal midbrain, surrounded by the fourth ventricle. This nucleus is one of the main sources of norepinephrine in the brain, and is composed of mostly medium-sized neurons. Melanin granules inside the LC contribute to its blue color; it is thereby also known as the nucleus pigmentosus pontis, meaning "heavily pigmented nucleus of the pons".

26. Locus ceruleus

27. hippocampus

28. Thalamus

29. Dopamine is also classed as a monoamine neurotransmitter and is concentrated in very specific groups of neurons collectively called the basal ganglia. Dopaminergic neurons are widely distributed throughout the brain in three important dopamine systems (pathways): the nigrostriatal, mesocorticolimbic, and the tuberohypophyseal pathways. A decreased brain dopamine concentration is a contributing factor in Parkinsonﾕs disease, while an increase in dopamine concentration has a role in the development of schizophrenia.

30. Biosynthesis of Epinephrine

31. Although dopamine is synthesized by only several hundred thousand cells, it fulfils an exceedingly important role in the higher parts of the CNS. These dopaminergic neurons can be divided into three subgroups with different functions. The first group regulates movements: a deficit of dopamine in this (nigrostriatal) system causes Parkinson's disease which is characterized by trembling, stiffness and other motor disorders, while in the later phases dementia can also set in. 
The second group, the mesolimbic, has a function in regulating emotional behavior. The third group, the mesocortical, projects only to the prefrontal cortex. This area of cortex is involved with various cognitive functions, memory, behavioral planning and abstract thinking, as well as in emotional aspects, especially in relation to stress. The earlier mentioned reward system is part of this last system. 
The nucleus accumbens is an important intermediate station here. Disorders in the latter two systems are associated with schizophrenia.

32. Dopamine and Parkinson’s Disease • In patients with Parkinson’s disease, there is disease or degeneration of the so-called basal ganglia in the deeper grey matter of the brain, particularly of that part known as the substantia nigra.

33. Parkinson’s Disease • The substantia nigra, which connects with the striatum (caudate nucleus and globus pallidus), contains black pigmented cells and, in normal individuals, produces a number of chemical transmitters, the most important of which is dopamine. Transmitters are chemicals that transmit, that is, pass on, a message from one cell to the next, either stimulating or inhibiting the function concerned; it is like electricity being the transmitter of sound waves in the radio. Other transmitters include serotonin, somatostatin and noradrenaline. In Parkinsonﾕs disease, the basal ganglia cells produce less dopamine, which is needed to transmit vital messages to other parts of the brain, and to the spinal cord, nerves and muscles.

34. In Parkinson’s disease, there is degeneration of the substantia nigra which produces the chemical dopamine deep inside the brain

35. Parkinson’s Disease • The basal ganglia, through the action of dopamine, are responsible for planning and controlling automatic movements of the body, such as pointing with a finger, pulling on a sock, writing or walking. If the basal ganglia are not working properly, as in Parkinson’s disease patients, all aspects of movement are impaired, resulting in the characteristic features of the disease ﾐ slowness of movement, stiffness and effort required to move a limb and, often, tremor. • Dopamine levels in the brain’s substantia nigra do normally fall with ageing. However, they have to fall to one-fifth of normal values for the symptoms and signs of parkinsonism to emerge.

36. Parkinson’s Disease • http://www.parkinsonshealth.com/AboutPD/Section.aspx?SectionId=798d598e-2a1c-4747-ac81-cd92f475744b • http://www.medindia.net/animation/parkinsons_disease.asp

37. History • James Parkinson (1755-1824), while best remembered for the disease state named after him by Charcot, was a man of many talents and interests. Publishing on chemistry, paleontology and other diverse topics, he was, early in his career, a social activist championing the rights of the disenfranchised and poor. His efforts in this area were enough to result in his arrest and appearance before The Privy Council in London on at least one occasion. In collaboration with his son, who was a surgeon, he also offered the first description, in the English language, of a ruptured appendix.

38. History of Parkinson’s Disease • His small but famous publication, "Essay on the Shaking Palsy", appeared in 1817, 7 years before his death in 1824. The clinical description of 6 patients was a remarkable masterpiece testifying to his prodigious powers of observation for most of the 6 were never actually examined by Parkinson himself; rather, they were simply observed walking on the streets of London.

39. Treatment of Parkinson’s Disease • Since PD is related to a deficiency of dopamine, it would be appropriate to administer dopamine • Problem: Dopamine does not cross BBB, since it is too polar

40. History of Treatment of PD • Arvid Carlsson (b. January 25, 1923) is a Swedish scientist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease. Carlsson won the Nobel Prize in Physiology or Medicine in 2000 along with co-recipients Eric Kandel and Paul Greengard.Carlsson was born in Uppsala, Sweden, son of Gottfrid Carlsson, historian and later professor of history at the Lund University, where he began his medical education in 1941. Although Sweden was neutral during World War II, Carlsson's education was interrupted by several years of service in the Swedish Armed Forces. In 1951, he received his M.L. degree (the equivalent of the American M.D.) and his M.D. (the equivalent of the American Ph.D.). He then became a professor at the University of Lund. In 1959 he became a professor at the G嗾eborg University.In the 1950s, Carlsson demonstrated that dopamine was a neurotransmitter in the brain and not just a precursor for norepinephrine, as had been previously believed. He developed a method for measuring the amount of dopamine in brain tissues and found that dopamine levels in the basal ganglia, a brain area important for movement, were particularly high. Carlsson then showed that giving animals the drug reserpine caused a decrease in dopamine levels and a loss of movement control. These effects were similar to the symptoms of Parkinson's disease. By administering to these animals L-Dopa, a precursor to dopamine, he could alleviate the symptoms. These findings led other doctors try L-Dopa with human Parkinson's patients and found it to alleviate some of the symptoms in the early stages of Parkinson's. L-Dopa is still today the cornerstone of Parkinson therapy.

41. Biosynthesis of Epinephrine

42. Wait a minute! • If dopamine is too polar to cross the BBB, how can L-DOPA cross it?

43. Answer! • L-DOPA is transported across the BBB by an amino acid transport system (same one used for tyrosine and phenylalanine) • Once across, L-DOPA is decarboxylated to dopamine by Dopa Decarboxylase (DDC).

44. This is an example of a “prodrug”, that is, a molecule that is a precursor to the drug and is converted to the actual drug at an appropriate place in the body.

45. In actual practice, L-DOPA is almost always coadminstered together with an inhibitor of aromatic L-amino acid decarboxylase, so it doesn’t get converted to dopamine before it crosses the BBB. • The inhibitor commonly used is carbidopa, which does not cross the BBB itself. • The inhibitor also prevents undesirable side effects of dopamine release into the PNS, including nausea.

46. SINEMET(CARBIDOPA-LEVODOPA)DESCRIPTIONSINEMET* (Carbidopa-Levodopa) is a combination of carbidopa and levodopa for the treatment of Parkinson's disease and syndrome. • http://www.learningcommons.umn.edu/neuro/mod6/carb.html

47. Endorphin • Endorphins (or more correctly Endomorphines) are endogenous opioid biochemical compounds. They are peptides produced by the pituitary gland and the hypothalamus in vertebrates, and they resemble the opiates in their abilities to produce analgesia and a sense of well-being. In other words, they might work as "natural pain killers." Using drugs may increase the effects of the endorphins.

48. Serotonin • Although the CNS contains less than 2% of the total serotonin in the body, serotonin plays a very important role in a range of brain functions. It is synthesised from the amino acid tryptophan.Within the brain, serotonin is localised mainly in nerve pathways emerging from the raphe nuclei, a group of nuclei at the centre of the reticular formation in the
Midbrainﾊ, ponsﾊ and medulla. These serotonergic pathways spread extensively throughout the brainstemﾊ, the cerebral cortexﾊ and the spinal cordﾊ. In addition to mood control, serotonin has been linked with a wide variety of functions, including the regulation of sleep, pain perception, body temperature, blood pressure and hormonal activity.Outside the brain, serotonin exerts a number of important effects, particularly involving the gastrointestinal and cardiovascular systems.