Pharmacology of the Central Nervous System (CNS) Dr. Sabry Attia. November 2006

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1 Pharmacology of the Central Nervous System (CNS) Dr. Sabry Attia November 2006

2 Neurodegenerative disease Neurodegenerative disease is a condition which affects brain function. They are result from deterioration of neurons. Changes in these cells cause them to function abnormally, eventually bringing about their death. With few exceptions, CNS neurones cannot divide, nor can they regenerate when their axons are interrupterd. Thus, any pathological process causing neuronal loss (by excito-toxicity, oxidative stress or apoptosis) generally has irreversible consequences. Neurodegenerative diseases are divided into two groups: 1. Conditions causing problems with movements (such as Parkinson s disease and Huntington's chorea). 2. Conditions related to memory and dementia (such as Alzheimer s disease).

3 Parkinson's disease After injury, the CNS can mobilize a number of responses. A: If neurons degenerate B: When an axon is severed The Parkinson's disease involves a progressive movement disorder of the extrapyramidal system, which controls and adjusts communication between neurons in the brain and muscles in the human body.

4 Notable Parkinson's sufferers Symptoms (i) (ii) (iii) (iv) The cardinal features of Parkinson's disease are (TRAP) Tremor or trembling in hands, arms, legs, jaw, and face; (pill-rolling), mainly at rest. Rigidity or stiffness of the limbs and trunk (increased tone or stiffness in the muscles), which leads to difficulties in walking, writing, speaking and masking of facial expression. Akinesia (lack of spontaneous movement) /bradykinesia (a slowness in initiating and executing movements). Posture and instability or impaired balance and coordination. Causes Often idiopathic, but may follow stroke, virus infection, can be drug-induced (neuroleptic drugs, reserpine, alpha-methyl dopa and cholinomimitics). It can also induce by the mepridine analogue MPTP (converted to a toxic metabolite, MPP + by MAO-B), a neurotoxin affecting dopamine neurons in the corpus striatum frozen addict syndrome.

5 MPTP-Induced Parkinsonian Syndrome. The "best" animal model for investigating Parkinson's disease to date. MPP+ appears to support the occurrence of oxidative stress, impairs ATP formation and of intracellular Ca2+. BBB, bloodbrain barrier; MPDP+, 1-methyl-4-phenyl-2,3-dihydropyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; MPP+, its four-electron oxidation product; MAO, monoamine oxidase.

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8 The biosynthetic pathway for the catecholamine neurotransmitters. The amino acid tyrosine is the precursor for all three catecholamines. The first step in this reaction pathway, catalyzed by tyrosine hydroxylase, is rate-limiting.

9 Dopamine receptor types There are two main families of dopamine receptor, D1 and D2, linked, respectively, to stimulation and inhibition of adenylate cyclase. The D1 family comprises D1 and D5 subtypes (excitatory). The D2 family comprises D2, D3 and D4 subtypes (inhibitory). The known functions of dopamine appear to be mediated mainly by receptors of the D2 family. Effect of dopamine on intracellular signaling pathways. Stimulation of receptors by agonists can change enzyme activities as well as gene expression. Adenylyl cyclase catalyzes the conversion of ATP into camp, which in turn causes dissociation of the regulatory and catalytic subunits of protein kinase A. The activated catalytic subunit catalyzes conversion of protein substrates into phosphoproteins. This is turn can lead to a short-term response within the cell or activate transcription factors (TF) which enter the nucleus and alter gene expression.

10 Muscarinic receptor types Muscarinic receptors M2 and M4 are inhibitory and increasing K+ conductance, whereas M1, M3 and M5 are excitatory. Ach interacts with a muscarinic receptor of the subtypes indicated to induce various responses. The M2 and M4 muscarinic acetylcholine receptors (machrs) interact with the a subunit of GTP-binding protein, Gi. When ACh binds, inhibits adenylyl cyclase (AC). The M1, M3 and M5 machrs interact with GTP-binding proteins and activate phosphoinositidespecific phospholipase C (PI-PLC). The M2 and M4 machrs regulate inwardly rectifying K+ channels. inositol trisphosphate (IP3 ) diacylglycerol (DAG). IP3 is generated from phosphatidylinositol bisphosphate (PIP2 ). NE, norepinephrine; b-adrr, b-adrenergic receptor; PI, phosphatidylinositol; PIP, phosphatidylinositol-4-phosphate.

11 A. The distribution in the human brain of dopaminergic neurons The direct pathway contains two inhibitory GABAergic synapses: A or A' (dark orange) is between the striatum and the pallidum, or the substantia nigra (SNr); B or B' (light orange) is between the pallidum or SNr and the thalamus. Activation of this pathway produces disinhibition of the excitatory glutamatergic thalamic input to the sensory, motor and associated areas of the cortex. The indirect pathway, a, b, c (gray), includes one excitatory glutamatergic and three inhibitory GABAergic synapses: a is between the striatum and the pallidum; b is between the pallidum and the subthalamic nucleus, and the subthalamic nucleus projects excitatory fibers to the pallidum; and c is between the pallidum and the thalamus. In contrast to the direct pathway, the three inhibitory synapses (a, b, c) result in net inhibition (inhibition of disinhibition) of the thalamic-cortical projections when the indirect circuit is activated. The activity in the two pathways depends, among other factors, on the balance of excitatory and inhibitory receptors activated on the striatal GABAergic neurons. D1 excitatory receptors are found mainly on the direct pathway and D2 inhibitory receptors, mainly on the indirect path. The dopaminergic innervations of the striatum from the substantia nigra and the intrastriatal cholinergic neurons are among the most important modulators of these circuits. ACh, acetylcholine; Sup coll, superior colliculus; Glu, glutamate; n, nuclei.

12 Dopaminergic Pathways in CNS 1. Nigrostriatal pathway 2. Mesolimbic/Mesocortical pathway 3. Tuberohypophyseal pathway

13 Diagnosis CT apparatus in a hospital Magnetic resonance imaging (MRI) Positron emission tomography (PET)

14 Huntington's disease Huntington's chorea (HD) is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory (amnesia). It is starting in adulthood and causing rapid deterioration and death. The disease predominantly strikes the striatum. Atrophy or degeneration of the caudate nucleus can be seen on CT, MRI studies. Death occurs (on average) years after the onset (from aspiration pneumonia). The causative gene is located on chromosome 4. The product of this gene is a cytoplasmic protein called huntingtin. The continuous aggregation of huntingtin molecules in neuronal cells gives rise to cell death. Neurochemically, there is marked of GABA throughout the basal ganglia; there is also levels of substance P and enkephalins. Dopamine content of the striatum was normal or slightly, while there was a 75% reduction in the activity of glutamic acid decarboxylase, the enzyme responsible for GABA synthesis. It is believed that the loss of GABA-mediated inhibition in the striatum produces a hyperactivity of dopaminergic synapses, so the syndrome is in some senses a mirror image of parkensonism, dopamine antagonists being effective in reducing the involuntary movements, while drugs such as levodopa and bromocriptine make them worse. Signs/Symptoms Classic triad: 1. Chorea (jerky, random, uncontrollable, rapid movements) of the face and body in general and unsteady walking. 2. Loss of cognitive ability (dementia; thinking, speaking), and personality disorders. 3. Family history (Teeth grinding, Facial grimacing, Difficulty swallowing, Depression). Treatment ( dopamine action) 1. Neuroleptics/dopamine receptor blockers as Haloperidol, Fluphenazine, Perphenazine (tardive dyskinesia). 2. Presynaptic dopamine depleters as Reserpine and tetrabenazine (hypotension). 3. Agents for treatment of depression, psychosis, irritability: Clozapine, Fluoxetine, TCAs, Carbamazepine. Attempts to replace the deficiency in GABA by treating with GABA- mimetic agents have been unsuccessful. EPA, an Omega-3 fatty acid, has been shown to slow and possibly reverse the progression of the disease. Recently, it was found that a simple sugar called tre-halose can alleviate symptoms in genetically modified mice, giving hope for a treatment.

15 Alzheimer's disease Alzheimer's disease is a common age-related dementia (loss of intellectual ability), distinct from vascular dementia associated with brain infarction. Some of the most frequently observed symptoms of the disease include a progressive inability to remember facts and events and, later, to recognize friends and family. The main pathological features of Alzheimer's disease comprise amyloid plaques (deposition of an abnormal toxic protein outside nerve cells), neurofibrillary tangles (accumulation of abnormal protein filaments inside nerve cells) and a loss of cholinergic neurons. Neurochemistry. The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated. Prevention NSAIDs like ibuprofen and aspirin may delay the onset, and lower the ultimate risk, of Alzheimer s disease. The combination of vitamins E and C, vitamin B and folic acid, might, over time, sharply reduce the risk of the disease. EPA, an Omega-III fatty acid, has been shown to slow and possibly reverse the progression of the disease The natural chemical curcumin (antioxidant and a powerful anti-inflammatory), reduces Alzheimer's incidence in a mouse model and actually dissolves human senile plaques (beta amyloid) in the test tube. Treatment There is no cure, although there are drugs which temporarily reduce neurotransmitter degradation and alleviate some of the symptoms of the disease. 1. Acetylcholinesterase inhibitors:tacrine (hepatotoxic; no longer clinically used), donepezil, galantamine and rivastigmine (marketed as Exelon). 2. NMDA antagonists; Memantine. Notable Alzheimer's sufferer