neuroprotection for the new millennium : matchmaking pharmacology and technology

114

Neuroprotection for the New Millennium

Matchmaking Pharmacology and Technology

RUSSELL J. ANDREWS

NASA Ames Research Center, Moffett Field, California, U.S.A.

Department of Neurosurgery, Stanford University Medical Center, Stanford, California, U.S.A.

Division of Neurosurgery, Texas Tech University Health Sciences Center, El Paso, Texas, U.S.A.

A

BSTRACT

: A major theme of the 1990s in the pathophysiology of nervous sys-tem injury has been the multifactorial etiology of irreversible injury. Multiplecauses imply multiple opportunities for therapeutic intervention—hence theabandonment of the “magic bullet” single pharmacologic agent for neuroprotec-tion in favor of pharmacologic “cocktails”. A second theme of the 1990s has beenthe progress in technology for neuroprotection, minimally- or non-invasive mon-itoring as well as treatment. Cardiac stenting has eliminated the need, in manycases, for open heart surgery; deep brain stimulation for Parkinson's disease hasoffered significant improvement in quality of life for many who had exhaustedcocktail drug treatment for their disease. Deep brain stimulation of the subtha-lamic nucleus offers a novel treatment for Parkinson’s disease where a techno-logical advance may actually be an intervention with effects that are normallyexpected from pharmacologic agents. Rather than merely “jamming” the ner-vous system circuits involved in Parkinson’s disease, deep brain stimulation ofthe subthalamic nucleus appears to improve the neurotransmitter imbalancethat lies at the heart of Parkinson’s disease. It may also slow the progression ofthe disease. Given the example of deep brain stimulation of the subthalamicnucleus for Parkinson’s disease, in future one may expect other technological or“hardware” interventions to influence the programming or “software” of thenervous system’s physiologic response in certain disease states.

K

EYWORDS

: Brain stimulation; Excitotoxic injury; Minimally invasive surgery;Movement disorders; Neuroprotection; Parkinson’s disease; Subthalamic nucleus.

INTRODUCTION

Four years ago at the Third International Conference on Neuroprotective Agents(ICNA),

1

I presented evidence to support the concept that neuroprotection, in thespecific instance of intraoperative neuroprotection, would require a pharmacologic“cocktail”. A single agent “magic bullet” was simply naïve given the increasing com-plexity of nervous system injury, in terms of events occurring simultaneously as well

Address for correspondence: Russell J. Andrews, Division of Neurosurgery, Texas TechUniversity, Health Sciences Center, 4800 Alberta, El Paso, TX 79905, U.S.A., Voice: 915-545-6676; fax: 915-545-7584.

[email protected]

115ANDREWS: NEUROPROTECTION: PHARMACOLOGY AND TECHNOLOGY

as sequentially. The failure in the early 1990s of a number of large clinical trialsinvolving a single pharmacologic agent for the treatment of stroke and head injury ledto several papers advocating a cocktail approach to pharmacologic neuroprotection.

2,3

Two years ago at the Fourth ICNA,

4

my theme was technological advances over-shadowing pharmacologic advances in the search for intraoperative neuroprotection.In recent years our ability to perform operations with efficacy and safety hasimproved, largely because of dramatic technological progress. Comparatively littleprogress has come from developments in pharmacologic neuroprotective agents usedintraoperatively or perioperatively. Putative noxious agents—lurking for minutes tohours to days after injury to the nervous system—proliferate in daunting fashion. Theischemic cascade seemingly verifies, for the complexity of nervous system injury,Moore’s Law for computer chips: that there is a doubling of processing speed every18 months. The examples of coronary artery stenosis surgery and surgery for Parkin-son’s disease were used to illustrate the common “agent” of the computer outstrip-ping the increasingly enigmatic or secret “agent” of nervous system pathophysiology.

For this, the inaugural ICNA of the new millennium, I carry the unfolding relationbetween pharmacology and technology one step further. With the advent of implant-able electrostimulation devices to restore neurological function after stroke (e.g., aparalyzed limb or blindness),

5

the use of such devices for neuroprotection is feasiblein certain situations. To provide continuity with the paper presented at the FourthICNA, I consider the example of Parkinson’s disease.

PHARMACOLOGIC COCKTAIL NEUROPROTECTION—THE SOFTWARE

Multifactorial etiologies for various human pathophysiologic processes might beconsidered a pervasive theme of the 1990s. Consider the following quotations:

“…the complex pathophysiology of…may require a multiple, simultaneous,or sequential drug-treatment approach. …Therapy directed at only one of theprocesses involved in…may have only modest benefits at best… a series ofsingle-agent trials might reject agents of limited efficacy in isolation that areeffective in combination with other drugs.”

—Adams 1995 (Ref. 3)

“…is not a single disease, but a very complex condition comprising a large va-riety of local and systemic…responses. Therefore, we propose that a combina-tion of several therapies or multifunctional agents, directed at various phasesof…might meet with more success than recent trials with single therapies.”

—Karima 1999 (Ref. 6)

“Recent failures of so-called ‘magic bullets’ in randomized clinical trialssuggest that multi-modality therapy may be required… If there are multiplemediators and factors involved in…then multiple agents may be needed.”

—Baue 1998 (Ref. 7)

“…the greatest challenge of the future will lie in using new markers to directpatient treatment. It is unlikely that any single marker will have sufficientsensitivity or specificity to alter treatment choice with certainty. Therefore,future evaluations should focus on developing nomograms combining mul-tiple markers…”

—Reiter 1999 (Ref. 8)

116 ANNALS NEW YORK ACADEMY OF SCIENCES

“Treatment of patients with established…is still largely supportive and hasmade little impact on the patient mortality rate over the past 20 years. Futuretreatment strategies must focus on multimodality combination therapy aimedat specifically suppressing excessive activation of…while preserving…nor-mal…defenses.”

—Deitch 1999 (Ref. 9)

“…it may be important to test a cocktail of drugs with different therapeutictargets. …rather than performing a limited number of costly clinical trialsthat test single agents in large numbers of unselected cases in search of smalland incremental benefits, it may be more profitable to use the same dollarsto perform a large number of clinical trials that test a larger number of agentsand combination of agents…”

—Marsden 1998 (Ref. 10)

Although very similar in message, the above quotes describe quite differentprocesses:1. An editorial entitled: “Acute stroke treatment trials in the United States: rethink-ing strategies for success”;2. A review of sepsis entitled: “The molecular pathogenesis of endotoxic shockand organ failure”;3. A review of systemic inflammatory response and multiple organ failure;4. An editorial considering methodologies for prostate cancer diagnosis;5. A review entitled: “Prevention of multiple organ failure”;6. A review of Parkinson's disease entitled: “The causes of Parkinson’s disease arebeing unraveled and rational neuroprotective therapy is close to reality”.

However, beneath the appearance of disparate disease processes for stroke, septicshock and multiple organ failure, cancer, and a neurodegenerative process such asParkinson’s disease runs the common thread of host defense mechanisms being inap-propriate—either inadequate (in the case of cancer) or excessive (stroke, neurode-generative diseases, and sepsis/multiple organ failure).

Pharmacologic interventions can be considered the “software” that directs ormodulates the host response to insult. The theme developed in the 1990s has beenthe necessity of multiple agents for effective therapy, given the complexity of thepathophysiological processes involved. The art and science of neuroprotection in thefirst decade of the new millennium will depend significantly on how well we candirect an increasing number of magic bullet drugs to their targets with as little col-lateral damage as possible.

TECHNOLOGICAL NEUROPROTECTION—THE HARDWARE

The potential technological advances benefitting neuroprotection are myriad:1. Imaging techniques such as ultrasound (US), computed tomography (CT), func-tional magnetic resonance imaging (fMRI), MR spectroscopy (MRS), and imagefusion (e.g., US, CT, and/or MRI).2. Minimally invasive surgical techniques (e.g., endoscopic or laparoscopic sur-gery, and endovascular techniques such as stenting).


3. Robotic and other automated surgical techniques to minimize human error orhuman limitations (e.g., the need for direct vision and tactile feedback, and thedrawback of physiologic tremor for precise surgery in ophthalmology and neuro-surgery).

Another application of technology to neuroprotection and neurorestoration is thedevelopment of implantable devices to preserve, improve, or restore functionality.This can take the form of techniques to bridge or bypass the region of nervous systeminjury, for example neurotrophic electrodes placed into the motor cortex that allowa patient with the locked-in syndrome to communicate by altering brain electricalactivity.

5

Another example is the use of stereotactic techniques to implant adrenaltissue precisely in the brain of a patient with Parkinson’s disease. A third example,directly relevant to neuroprotection, is the use of chronic electrical stimulation as aneuroprotective agent, discussed here in the context of Parkinson’s disease.

THE PATHOPHYSIOLOGY OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is a degenerative disorder of the nervous system thatwas first described by the English physician James Parkinson in 1817. It affects morethan one million people in the North America, its incidence increases with increasingage, and the mortality rate among those affected with PD is two to five times that ofage matched controls.

11

The basic pathophysiology of PD is reasonably well understood, and its treatmenthas extensive roots in both pharmacologic and surgical interventions.

11,12

Thepathological hallmark of PD is a loss of dopaminergic neurons in the substantia nigracompacta (SNc). Details of the effect of the loss of dopamine on the various nucleiinvolved in Parkinsonian movement disorders are illustrated in F

IGURE

1, where(F

IG

. 1A) diagrams the normal situation and (F

IG

. 1B) the situation in PD. Note theseparate direct and indirect pathways (the latter via the subthalamic nucleus [STN])by which a decrease in dopamine can affect the circuit of nuclei involved in Parkin-sonian movement disorders.

Among the etiologies of PD are idiopathic, postencephalitic (encephalitis lethar-gica or von Economo’s disease), and drug induced. Drug induced PD (DIPD) occursfollowing the use of dopamine receptor blocking agents, although the list of pharma-cologic agents that can cause DIPD includes—in addition to dopamine receptorblockers—the false neurotransmitter methyldopa, antiemetics (e.g., chlorprom-azine), anticonvulsants (e.g., valproic acid), cholinomimetics (e.g., bethanecol),sympatholytics (e.g., reserpine), and calcium channel blockers (e.g., flunarizine).

13

Although DIPD is relatively common among those taking one of the offendingdrugs, it fortunately resolves in most cases on discontinuing use of the drug.

Idiopathic PD may begin before age 40, and unfortunately runs a relentlessly pro-gressive course in most cases. The cardinal findings are tremor, bradykinesia, rigid-ity, and postural instability. The severe disability of PD led to many surgicalexplorations in the search for relief from the movement disorders, with stereotacticlesioning of the globus pallidus or thalamus proving to be of considerable benefit inthe 1950s and 1960s.


The discovery that the dopamine precursor L-dopa, which readily crosses theblood–brain barrier, can ameliorate the dopamine deficit in PD resulted in a dramaticreduction in the number of surgical procedures for PD when L-dopa came into wide-spread clinical use in the late 1960s. For approximately 20 years after the late 1960s,

FIGURE 1. Model of the basal ganglia in persons with normal motor control (A) andParkinson’s disease (B). Plus signs indicate excitation; minus signs inhibition. Arrow widthin (B) indicates the functional activity change in each pathway (change in neuronal firingrate) compared with normal activity. The size and outline of each box in (B) indicate theactivity of the brain region compared with normal activity. Dashed lines and arrows indicatethe dysfunctional nigrostriatal dopamine system in PD. The neurotransmitters used in eachpathway are circled. VA/VL, ventral anterior and ventrolateral; GABA, g-aminobutyric acid.(Reprinted from Ref. 11 with permission from the New England Journal of Medicine.)


only a few major academic medical centers routinely performed stereotactic proce-dures for PD and other movement disorders.

14

L-dopa and other dopaminergicagents such as bromocriptine and pergolide, monoamine oxidase inhibitors such asdeprenyl, and various anticholinergic agents all demonstrated varying degrees ofsuccess in treating PD.

FIGURE 2. Schematic of the deep brain stimulator. Note the electrode placed into thethalamic or subthalamic region, the connecting wires placed subcutaneously, and the stimula-tor/battery placed subcutaneously inferior to the clavicle (Figure provided by Medtronic, Inc.)


These pharmacologic treatments for PD have several drawbacks, however. All ofthe agents appear to be symptomatic rather than curative in their efficacy. Sideeffects—notably nausea, confusion, and hallucinations—are common to all as well.Their benefit is not universal, in that only 1/2 to 2/3 of patients experience significantbenefit. Bradykinesia and rigidity usually respond better than tremor. Perhaps mostimportantly, within two to five years of beginning L-dopa therapy (usually combinedwith the peripheral decarboxylase inhibitor carbidopa) the majority of patients expe-rience a gradual but progressive decrease in efficacy. This decrease takes the form ofeither a diurnal variation in, or recurrence of, the Parkinsonian dyskinesias and rigid-ity (off stage)—alternating with periods of relative mobility (on stage). The failureof pharmacologic therapy to be an effective long term treatment for PD, togetherwith improvements in neuroimaging (CT and MRI), stereotactic techniques for neu-rosurgery, and electrophysiologic recording, all served to rekindle interest in the sur-gical treatment of PD in the late 1980s.

The original surgical intervention used radiofrequency heating of a microelec-trode to ablate either the ventrointermediate nucleus of the thalamus or the globuspallidus interna (GPi). In the late 1980s, Benabid in France pioneered the use of animplantable programmable stimulator to electrically “ablate” the region of interestin the thalamus or globus pallidus.

15

To effectively ablate, the stimulation must berelatively high frequency (100 to 200 Hz), with a voltage of 1 V to 3 V. The stimula-tor, derived from cardiac pacemakers, had been used during the early 1980s for epi-dural spinal cord stimulation—as well as by a few neurosurgeons in academicsettings for deep brain stimulation (particularly for intractable chronic pain syn-dromes). In its present configuration, the microelectrode is stereotactically placed inthe region of interest and connected by wires under the scalp and skin of the neck tothe stimulator (a microprocessor and battery) placed—like a cardiac pacemaker—subcutaneously in the region of the clavicle (see F

IGURE

2).

Extensive testing of deep brain stimulation (DBS) of the thalamus in particular—for Parkinsonian tremor as well as essential tremor—took place in Europe and theUS during the late 1980s to mid 1990s. Food and Drug Administration (FDA)approval was granted in 1997 to market a device in the US for DBS of the thalamusas a treatment for contralateral tremor. In the early 1990s, Benabid and others foundthat stimulation of the subthalamic nucleus (STN) was effective in treating not onlythe tremor of PD, but the other symptoms (bradykinesia, rigidity) as well.

16

Present-ly the STN is the site of choice for most patients undergoing DBS for PD; the vastmajority of patients benefit most from bilateral STN DBS placement.

SUBTHALAMIC NUCLEUS STIMULATION:NEUROPROTECTIVE MARRIAGE

The effect of STN stimulation (DBS)—where stimulation is considered equiva-lent to ablation or disruption of the normal electrochemical circuitry—is illustratedin F

IGURE

3.

11

Note that one of the effects of PD is increased firing activity of theSTN neurons, which in turn results in an excitatory effect on the SNc. STN DBS hasan advantage over GPi DBS (or GPi ablation) in that it modulates the response of


both the GPi and the substantia nigra reticulata (SNr). This likely accounts for thegreater effectiveness of STN DBS in most patients with PD.

It has recently been argued that STN DBS may actually be neuroprotective inaddition to providing symptomatic relief for patients with PD.

17

This marriage ofimplanted hardware to alter the neurochemical processes that underlie the loss ofdopaminergic neurons in the SNc warrants consideration in some detail. The follow-ing is in essence a summary of the evidence marshalled by Rodriguez

et al.

17

The STN is the central nucleus in the glutamatergic excitatory pathways in thebasal ganglia, as shown in F

IGURE

4.

17

The argument in favor of STN inhibition (e.g.,by electrical stimulation) runs as follows:

1. SNc dopaminergic neurons can exhibit a bursting type discharge pattern whichis associated with dopamine release.

2. STN excitation leads to increased SNc dopaminergic neuron bursting. Only amodest increase in STN firing is necessary—in Parkinsonian monkeys the STN dis-charge rate is only 29

%

greater than controls.

3. The STN-induced increase bursting in SNc dopaminergic neurons leads to stresson an already tenuous SNc, that is to say excitotoxic aggravation of the loss of SNcdopaminergic neurons.

The argument that excitotoxic injury is important—if not essential—to the neu-rodegeneration in Parkinson's disease is also readily summarized:1. Glutamate mediates toxicity in SNc dopaminergic neurons. In MPTP treatedmonkeys, NMDA antagonists have been shown to be neuroprotective.

FIGURE 3. Model of the basal ganglia in persons with Parkinson's disease followingsurgical intervention in the subthalamic nucleus. Legend and abbreviations as in FIGURE 1.Note that reducing the excessive excitatory activity of the STN reduces the over-activity ofboth components of the output of the basal ganglia, the GPi and the SNr. (Reprinted fromRef. 11 with permission from the New England Journal of Medicine.)


2. Glutamate induced toxicity is mediated in part by nitric oxide (NO). Agents thatinhibit NO mediated toxicity are neuroprotective in animal models of PD.3. A mitochondrial defect—mitochondrial complex 1 defect—may predispose SNcdopaminergic neurons to excitotoxic injury.

18

The defect leads to a loss of Mg

+

blockade of NMDA receptors, rendering the SNc dopaminergic neurons especiallyvulnerable by virtue of increased Ca

2+

entry.4. Decreasing the glutamatergic output of the STN by lesioning has been neuropro-tective—in terms of SNc dopaminergic neurons—in animal models of PD.5. There is experimental evidence that NO mediated toxicity is important in PD,and that SNc dopaminergic neurons may be especially vulnerable to NO, whereasother neurons may be protected (e.g., by increased levels of superoxide dismutase).

FIGURE 4. Schematic of the main glutamatergic pathways in the basal ganglia. Thesubthalamic nucleus (STN) has excitatory projections to the external and internal globuspallidus (GPe and GPi), the substantia nigra pars reticulata and pars compacta (SNpr andSNpc), the striatum (STR), and the pedunculopontine nucleus (PPN) in the brainstem.Glutamatergic projections to the STN arise from the cerebral cortex, the parafascicular andcentromedian (Pf-CM) nuclei of the thalamus, and the PPN. Glutamatergic projections tothe SNpc arise from the STN, the PPN, and the cerebral cortex. ACh, acetylcholine.(Reprinted from Ref. 17 with permission from the Annals of Neurology.)


Rodriguez

et al.

speculate that the following sequence of events can account forthe neurodegeneration in PD:

17

1. SNc dopaminergic neurons have an increased susceptibility to excitotoxic injurythat leads to apotosis in at least some of these neurons. The predisposing factors,which may be either inherited and/or acquired, are:

• an as yet undetermined vulnerability to oxidative stress (e.g., 5 in the previousparagraph)

• the mitochondrial complex 1 defect in 3 in the previous paragraph

2. The loss of SNc dopaminergic neurons leads to decreased striatal dopamine, thatin turn results in a decrease in inhibition of D

2

striatal neurons. This leads toincreased inhibition of the GPe, that in turn disinhibits the STN.3. Increased firing in the STN leads to glutamatergic excitation in SNc, as well asin SNr, GPi, and PPN.4. The increased glutamate in SNc leads to further loss of dopaminergic neuronsand, in turn, decreased striatal dopamine.5. A“vicious cycle” is created in which the STN is further disinhibited and the SNcdopaminergic neurons exposed to further excitotoxic injury.6. A some critical point—probably when 30 to 50

%

of dopaminergic neurons inthe SNc are lost—the symptoms of PD become manifest.7. Increased STN firing leads to glutaminergic excitotoxicity in SNr, GPi, andPPN—which may account for the late non-dopaminergic symptoms of PD—pos-tural instability, speech impairment, and autonomic dysfunction.

The above discussion affords several prospects for the treatment of PD in additionto the use of levodopa, interventions that might be neuroprotective in that they breakthe vicious cycle of STN disinhibition and the resultant excitotoxic stress on the SNcdopaminergic neurons in particular. Most obvious is the use of dopamine agonists,as has been variably accepted for many years by those treating patients with PD. Arecent article reporting that ropinirole, either alone or in conjunction with levodopa,is more effective than levodopa alone supports the use of certain dopamine agonistsin the treatment of PD.

19

The issue from a neuroprotection standpoint is whetherbeginning such medications early in PD can slow the progression of the disease.

Another approach is to use pharmacologic agents that attack the excitotoxic cas-cade. There are various options: (1) inhibition of glutamate release (e.g., lamotrigineand riluzole); (2) NMDA receptor antagonists to decrease the excitotoxic effect ofglutamate (the agents to date unfortunately have intolerable side effects); and/or (3)agents to oppose the effects of NO such as antioxidants. In time, this approach maybenefit from a careful combination drug therapy—a rational pharmacologic cocktail.The PD drug treatment of choice may prove to be an “alloy”.

Finally, there is deep brain stimulation of the STN. Although the mechanism bywhich stimulation of the STN at 100 to 200 Hz reduces the excitatory effect of theSTN output is uncertain, its benefit on all the cardinal symptoms of PD is clear nowthat hundreds of PD patients have undergone STN DBS—some for well over fiveyears.

The mechanism by which DBS affects the central nervous system is under debate.A simplistic explanation is that the stimulation jams the neural pathways, interrupt-ing a circuit, and thus providing the desired clinical effect. However, recent research


with brain slice preparations indicates that electrical stimulation in cortical gray mat-ter activates axonal branches rather than cell bodies.

20

If so, the overall effect ofDBS in regions that contain both axons passing through as well as cell bodies isuncertain. Additionally, the mechanism by which DBS decreases the firing rate in theSTN, for example, is unclear: depolarization blockade, orthodromic excitation, andantidromic activation are all possibilities.

21

Another explanation for the therapeuticeffect of DBS is stochastic resonance, where adding the regularity of high frequencyDBS as noise to the signal of the STN neurons results in an improved signal-to-noiseratio.

22

The future of DBS includes much uncharted and potentially productive territory.In addition to the hardware advances of more precise electrode placement and small-er electrodes (including microarrays), the benefits of varying the stimulation param-eters beyond those of frequency, amplitude, and duration remain for the most partunexplored. For example, varying the frequency (perhaps in conjunction with vary-ing the amplitude) may result in more effective inhibition. An intriguing possibilityis that the neurons in a nucleus such as the STN may be taught by DBS to alter theirfiring rates or behavior.

23

Finally, DBS may see application in the treatment not onlyof disorders that might be considered extensions of its current applications in move-ment disorders (e.g., the motor and vocal tics of Gilles de la Tourette’s syndrome

21

)but also in more novel situations such as epilepsy, obsessive compulsive disorders,and eating disorders.

23

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