Chapter 8: Neurodegenerative Diseases



Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmission process. Drugs affecting the CNS may act presynaptically by influencing the production, storage, release, or termination of action of neurotransmitters. Other agents may activate or block postsynaptic receptors. This chapter provides an overview of the CNS, with a focus on those neurotransmitters that are involved in the actions of the clinically useful CNS drugs. These concepts are useful in understanding the etiology and treatment strategies for the neurodegenerative disorders that respond to drug therapy: Parkinson disease, Alzheimer disease, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) (Figure 8.1).

Figure 8.1. Summary of agents used in the treatment of Parkinson disease, Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

Summary of agents used in the treatment of Parkinson disease, Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

Neurotransmission in the CNS

In many ways, the basic functioning of neurons in the CNS is similar to that of the autonomic nervous system described in Chapter 3. For example, transmission of information in the CNS and in the periphery both involve the release of neurotransmitters that diffuse across the synaptic space to bind to specific receptors on the postsynaptic neuron. In both systems, the recognition of the neurotransmitter by the membrane receptor of the postsynaptic neuron triggers intracellular changes. However, several major differences exist between neurons in the peripheral autonomic nervous system and those in the CNS.

The circuitry of the CNS is much more complex than that of the autonomic nervous system, and the number of synapses in the CNS is far greater. The CNS, unlike the peripheral autonomic nervous system, contains powerful networks of inhibitory neurons that are constantly active in modulating the rate of neuronal transmission. In addition, the CNS communicates through the use of more than 10 (and perhaps as many as 50) different neurotransmitters. In contrast, the autonomic nervous system uses only two primary neurotransmitters, acetylcholine and norepinephrine.

Synaptic Potentials

In the CNS, receptors at most synapses are coupled to ion channels. That is, binding of the neurotransmitter to the postsynaptic membrane receptors results in a rapid but transient opening of ion channels. Open channels allow specific ions inside and outside the cell membrane to flow down their concentration gradients. The resulting change in the ionic composition across the membrane of the neuron alters the postsynaptic potential, producing either depolarization or hyperpolarization of the postsynaptic membrane, depending on the specific ions that move and the direction of their movement.

A. Excitatory pathways

Neurotransmitters can be classified as either excitatory or inhibitory, depending on the nature of the action they elicit. Stimulation of excitatory neurons causes a movement of ions that results in a depolarization of the postsynaptic membrane. These excitatory postsynaptic potentials (EPSP) are generated by the following: 1) Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of sodium (Na+) ions.

2) The influx of Na+ causes a weak depolarization, or EPSP, that moves the postsynaptic potential toward its firing threshold. 3) If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released. This ultimately causes the EPSP depolarization of the postsynaptic cell to pass a threshold, thereby generating an all-or-none action potential. [Note: The generation of a nerve impulse typically reflects the activation of synaptic receptors by thousands of excitatory neurotransmitter molecules released from many nerve fibers.] Figure 8.2 shows an example of an excitatory pathway.

Figure 8.2. Binding of the excitatory neurotransmitter, acetylcholine, causes depolarization of the neuron.

Binding of the excitatory neurotransmitter, acetylcholine, causes depolarization of the neuron.

B. Inhibitory pathways

Stimulation of inhibitory neurons causes movement of ions that results in a hyperpolarization of the postsynaptic membrane. These inhibitory postsynaptic potentials (IPSP) are generated by the following: 1) Stimulation of inhibitory neurons releases neurotransmitter molecules, such as ?-aminobutyric acid (GABA) or glycine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of specific ions, such as potassium (K+) and chloride (Cl?) ions. 2) The influx of Cl? and efflux of K+ cause a weak hyperpolarization, or IPSP, that moves the postsynaptic potential away from its firing threshold. This diminishes the generation of action potentials. Figure 8.3 shows an example of an inhibitory pathway.

Figure 8.3. Binding of the inhibitory neurotransmitter, ?-aminobutyric acid (GABA), causes hyperpolarization of the neuron.

Binding of the inhibitory neurotransmitter, ?-aminobutyric acid (GABA), causes hyperpolarization of the neuron.

C. Combined effects of the EPSP and IPSP

Most neurons in the CNS receive both EPSP and IPSP input. Thus, several different types of neurotransmitters may act on the same neuron, but each binds to its own specific receptor. The overall resultant action is due to the summation of the individual actions of the various neurotransmitters on the neuron. The neurotransmitters are not uniformly distributed in the CNS but are localized in specific clusters of neurons, the axons of which may synapse with specific regions of the brain. Many neuronal tracts, thus, seem to be chemically coded, and this may offer greater opportunity for selective modulation of certain neuronal pathways.

Neurodegenerative Diseases

Neurodegenerative diseases of the CNS include Parkinson disease, Alzheimer disease, MS and ALS. These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. For example, Alzheimer disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Maynert, whereas Parkinson disease is associated with a loss of dopaminergic neurons in the substantia nigra. The most prevalent of these disorders is Alzheimer disease, estimated to have affected some 4 million people in 2000. The number of cases is expected to increase as the proportion of elderly people in the population increases.

Overview of Parkinson Disease

Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals.

A. Etiology

The cause of Parkinson disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum, parts of the brain’s basal ganglia system that are involved in motor control. The loss of dopamine neurons in the substantia nigra is evidenced by diminished overall uptake of dopamine precursors in this region, which can be visualized using positron-emission tomography and the dopamine analog fluorodopa (Figure 8.4).

Genetic factors do not play a dominant role in the etiology of Parkinson disease, although they may exert some influence on an individual’s susceptibility to the disease. It appears increasingly likely that an as-yet-unidentified environmental factor may play a role in the loss of dopaminergic neurons.

Figure 8.4. Positron-emission tomographic scan of the brain showing the difference in fluorodopa (FDOPA) levels between those with and without Parkinson’s disease.

Positron-emission tomographic scan of the brain showing the difference in fluorodopa (FDOPA) levels between those with and without Parkinson’s disease.

1. Substantia nigra

The substantia nigra, part of the extrapyramidal system, is the source of dopaminergic neurons (shown as red neurons in Figure 8.5) that terminate in the neostriatum. Each dopaminergic neuron makes thousands of synaptic contacts within the neostriatum and, therefore, modulates the activity of a large number of cells. These dopaminergic projections from the substantia nigra fire tonically rather than in response to specific muscular movements or sensory input. Thus, the dopaminergic system appears to serve as a tonic, sustaining influence on motor activity rather than participating in specific movements.

Figure 8.5. Role of substantia nigra in Parkinson disease.

Role of substantia nigra in Parkinson disease.

DA = dopamine; GABA = ?-aminobutyric acid; ACh = acetylcholine.

2. Neostriatum

Normally, the neostriatum is connected to the substantia nigra by neurons (shown as orange in Figure 8.5) that secrete the inhibitory transmitter GABA at their termini in the substantia nigra. In turn, cells of the substantia nigra send neurons (shown as red in Figure 8.5) back to the neostriatum, secreting the inhibitory transmitter dopamine at their termini. This mutual inhibitory pathway normally maintains a degree of inhibition of the two separate areas.

In Parkinson disease, destruction of cells in the substantia nigra results in the degeneration of the nerve terminals responsible for secreting dopamine in the neostriatum. Thus, the normal modulating inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative overactivity of acetylcholine by the stimulatory neurons (shown as green in Figure 8.5). This triggers a chain of abnormal signaling, resulting in loss of the control of muscle movements.

3. Secondary parkinsonism

Parkinsonian symptoms infrequently follow viral encephalitis or multiple small vascular lesions. Drugs such as the phenothiazines and haloperidol, whose major pharmacologic action is blockade of dopamine receptors in the brain, may also produce parkinsonian symptoms. These drugs should not be used in Parkinson disease patients.

B. Strategy of treatment

In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory cholinergic neurons that oppose the action of dopamine (see Figure 8.5). Many of the symptoms of parkinsonism reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. Therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effect of cholinergic neurons, thus reestablishing the correct dopamine/acetylcholine balance. Because long-term treatment with levodopa is limited by fluctuations in therapeutic responses, strategies to maintain CNS dopamine levels as constant as possible have been devised.

Drugs Used in Parkinson Disease

Currently available drugs offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease.

A. Levodopa and carbidopa

Levodopa [lee-voe-DOE-pa] is a metabolic precursor of dopamine (Figure 8.6). It restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20 percent of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects “wear off.”

Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of taking up exogenously administered levodopa and converting it to dopamine for subsequent storage and release. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa [kar-bi-DOE-pa], a dopa decarboxylase inhibitor that does not cross the blood-brain barrier.

Figure 8.6. Synthesis of dopamine from levodopa in the absence and presence of carbidopa, an inhibitor of dopamine decarboxylase in the peripheral tissues.

Synthesis of dopamine from levodopa in the absence and presence of carbidopa, an inhibitor of dopamine decarboxylase in the peripheral tissues.

GI = gastrointestinal.

1. Mechanism of action

a. Levodopa

Because parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine deficiency. Dopamine itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to dopamine in the brain (see Figure 8.6). Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension.

b. Carbidopa

Carbidopa, a dopa decarboxylase inhibitor, diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to fivefold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine.

2. Actions

Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism.

3. Therapeutic uses

Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson disease. In approximately two-thirds of patients with Parkinson disease, levodopa–carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. Patients then typically experience a decline in response during the third to fifth year of therapy.

4. Absorption and metabolism

The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response, which generally correlate with the plasma concentrations of levodopa, or perhaps give rise to the more troublesome “on-off” phenomenon, in which the motor fluctuations are not related to plasma levels in a simple way. Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility.

Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Large, neutral amino acids (for example, leucine and isoleucine) compete with levodopa for absorption from the gut and for transport across the blood-brain barrier. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual.

5. Adverse effects

a. Peripheral effects

Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone of the medulla (Figure 8.7). Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Hypotension may also develop. Adrenergic action on the iris causes mydriasis, and, in some individuals, blood dyscrasias and a positive reaction to the Coombs test are seen. Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine oxidation.

Figure 8.7. Adverse effects of levodopa.

Adverse effects of levodopa.

b. CNS effects

Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. These CNS effects are the opposite of parkinsonian symptoms and reflect the overactivity of dopamine at receptors in the basal ganglia. Levodopa can also cause mood changes, depression, psychosis, and anxiety.

6. Interactions

The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness (Figure 8.8). Concomitant administration of levodopa and monoamine oxidase inhibitors (MAOIs), such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. Therefore, caution is required when they are used simultaneously. In many psychotic patients, levodopa exacerbates symptoms, possibly through the buildup of central catecholamines.

In patients with glaucoma, the drug can cause an increase in intraocular pressure. Cardiac patients should be carefully monitored because of the possible development of cardiac arrhythmias. Antipsychotic drugs are generally contraindicated in parkinsonian patients, because these potently block dopamine receptors and produce a parkinsonian syndrome themselves. However low doses of certain “atypical” antipsychotic agents are sometimes used to treat levodopa-induced psychiatric symptoms.

Figure 8.8. Some drug interactions observed with levodopa.

Some drug interactions observed with levodopa.

MAO = monoamine oxidase.

B. Selegiline and rasagiline

Selegiline [seh-LEDGE-ah-leen], also called deprenyl [DE-pre-nill], selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses but does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin) unless given at above recommended doses, where it loses its selectivity. By, thus, decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain (Figure 8.9). Therefore, it enhances the actions of levodopa when these drugs are administered together. Selegiline substantially reduces the required dose of levodopa.

Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. However, if selegiline is administered at high doses, the selectivity of the drug is lost, and the patient is at risk for severe hypertension. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than midafternoon. (See Mechanism of action for the use of selegiline in treating depression). Rasagiline [ra-SA-gi-leen], an irreversible and selective inhibitor of brain monoamine oxidase Type B, has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetamine-like substance.

Figure 8.9.Action of selegiline (deprenyl) in dopamine metabolism.

Action of selegiline (deprenyl) in dopamine metabolism.

MAO B = monoamine oxidase Type B.