Seizure: European Journal of Epilepsy
Volume 19, Issue 6 , Pages 311-318, July 2010

Is elevated norepinephrine an etiological factor in some cases of epilepsy?

  • Paul J. Fitzgerald

      Affiliations

    • Corresponding Author InformationCurrent address: National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, Room 2N09, Bethesda, MD 20852-9411, USA. Tel.: +1 443 564 1306.

The Zanvyl Krieger Mind/Brain Institute, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, 338 Krieger Hall, 3400N Charles St, Baltimore, MD 21218, USA

Received 18 August 2009; received in revised form 1 April 2010; accepted 23 April 2010. published online 21 May 2010.

Article Outline

Abstract 

It is well established that the neurotransmitter norepinephrine (NE) has anticonvulsant properties. However, NE may also have proconvulsant properties under some conditions, both in animal epilepsy models and in humans. This paper examines the hypothesis that this neurotransmitter has proconvulsant properties, where much of the pharmaceutical evidence comes from rodent models. In assessing the elevated NE epilepsy hypothesis, the following seven lines of evidence are examined that include studies of: (1) antidepressants that raise the level of NE; (2) clonidine and other alpha 2 adrenergic agonist drugs that lower the level of NE; (3) prazosin and other drugs that affect alpha adrenoceptors; (4) propranolol and other drugs that affect beta adrenoceptors; (5) pheochromocytoma, which is a rare cancer of the adrenal glands that can boost NE levels; (6) comorbidity of epilepsy with bipolar disorder, hypertension, and obesity, where all four conditions may involve elevated NE; and (7) psychological stress, which is associated with increased release of NE. The body of evidence supporting the NE proconvulsant hypothesis is consistent with the notion that elevated, endogenous noradrenergic transmission is an etiological factor in some cases of epilepsy.

Keywords: Norepinephrine, Adrenoceptor, Tricyclic antidepressant, Desipramine, Clonidine, Prazosin, Propranolol, Proconvulsant, Anticonvulsant

 

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1. Introduction 

A large number of studies have demonstrated that the neurotransmitter norepinephrine (NE) has anticonvulsant properties.1 Many of these data involve rodent pharmaceutical studies of epilepsy (e.g., Ref. 2), and some recent evidence includes gene knockout studies in mice.3, 4, 5, 6 A ketogenic diet which boosts NE can have anticonvulsant effects in rodents,6 although boosting of NE is not necessarily this diet's anticonvulsant mechanism of action.7 A series of pioneering studies in dopamine beta-hydroxylase knockout mice (that lack NE) and alpha2a receptor knockout mice support an anticonvulsant role for NE in these animal models.3, 4, 5 Knockout of the NE transporter in mice, which results in elevated levels of synaptic NE, has an anticonvulsant effect.8, 9 It has also been argued that use of antidepressants that boost NE levels (and serotonin levels) is anticonvulsant, not proconvulsant.10 Whereas NE boosting tricyclic antidepressants may be proconvulsant at overdose levels, they may be anticonvulsant at low doses.11

While the above studies are valid and their conclusions may indeed be correct, there is also a significant body of evidence that NE is proconvulsant under certain conditions. NE is a “stress hormone” in the sympathetic nervous system, where it helps mediate the body's “fight or flight” response. In the brain, NE is associated with arousal and attention, where the NE boosting drug atomoxetine is used to treat attention deficit hyperactivity disorder (ADHD).12 If NE plays an “activating” role in the brain, this is consistent with it producing, under some conditions, excessive neural activity that may characterize epilepsy. The anticonvulsant drug valproic acid may deactivate neurons through the inhibitory neurotransmitter, GABA.13 And the anticonvulsant carbamazepine may decrease the cerebrospinal fluid (CSF) NE level in persons suffering from mania.14

The rest of the paper reviews literature that supports the NE proconvulsant hypothesis, while also presenting evidence in support of the anticonvulsant hypothesis. These two hypotheses are not mutually exclusive, and may each apply under different conditions in various organisms. The focus here is on pharmaceutical studies of NE manipulation (level and receptor drug effects) in rodent models of epilepsy. These studies, along with some human papers, comprise the first four lines of evidence in support of the NE proconvulsant hypothesis. Lines five and six comprise studies of conditions that may be characterized by elevated NE, such as bipolar disorder and hypertension, and their potential relationship with epilepsy. The seventh line examines the potential relationship between psychological stress, which is associated with increased release of NE, and epilepsy. While these lines of evidence support the NE proconvulsant hypothesis, they in many cases also support the NE anticonvulsant hypothesis.

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2. Literature search details 

This paper is based on selected keyword searches of the Pubmed database that were conducted as recently as March 28, 2010. The following combinations of keywords were used: (epilepsy, seizure)+(desipramine, tricyclic, reboxetine, atomoxetine, clonidine, prazosin, propranolol, pheochromocytoma, “cerebrospinal norepinephrine”). Additional searches were made using the terms: (epilepsy, seizure)+(comorbid, comorbidity)+(bipolar, hypertension, obesity, stress). Papers that were clearly relevant to the topic were included in this review.

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3. Results 

3.1. Norepinephrine boosting antidepressants 

A number of studies have shown that NE boosting antidepressants, such as the tricyclic antidepressants and the newer drugs reboxetine and atomoxetine, have proconvulsant and anticonvulsant effects, both in animal models and humans. The principal brain mechanism of two tricyclics, desipramine and nortriptyline, is boosting the level of extracellular NE via inhibition of the NE reuptake transporter.15 Other tricyclic antidepressants, such as imipramine and amitriptyline, are thought to boost significant amounts of both NE and serotonin,15 but in vivo these two drugs are rapidly metabolized into desipramine and nortriptyline, respectively.16 Rodent microdialysis studies indicate that imipramine boosts brain NE more strongly than it does serotonin.17 So the principal brain effect of all tricyclics may be boosting of extracellular NE.

The evidence from tricyclic epilepsy studies of rats, mice, cats, and humans supports both the proconvulsant and anticonvulsant hypotheses. Regarding proconvulsant data, in freely moving rats, imipramine and desipramine produced spike-wave complexes, spikes, and increased spindling.18 A rat study testing a variety of antidepressants found no effect on seizures after a single dose, whereas chronic administration of these drugs was proconvulsant.19 In rats presenting with spontaneous petit mal-like seizures, several tricyclics were tested and found to be proconvulsant.20 A pharmacological study in rats concluded that the NE boosting effects of imipramine are prominently involved in imipramine-induced seizures.21

Regarding anticonvulsant tricyclic results from rats, in the genetically epilepsy prone animal, several tricyclics acted as anticonvulsants in doses substantially lower than the toxic doses that produced spontaneous convulsions.2 In electrically kindled hippocampal seizures, several tricyclics significantly reduced afterdischarge duration, with amitriptyline being the most effective.22 A study of four tricyclics on amygdala-kindled seizures found that only amitriptyline had an anticonvulsant effect, and that was at near toxic doses.23

In epilepsy prone mice, desipramine potentiated the convulsant effects of NMDA.24 Therapeutic doses of desipramine in mice were markedly proconvulsant in a model of lidocaine-induced seizures.25 In a mouse study which showed anticonvulsant results, amitriptyline and imipramine provided protection against electroconvulsions, and they and desipramine potentiated the anticonvulsant effect of valproate.26 In mice, the tricyclic doxepin had anticonvulsant activity against maximal electroshock-induced seizures, as well as in several chemically-induced seizure models.27 A study in anesthetized cats found that various tricyclics produced epileptiform pathology in neocortex, hippocampus, and brainstem.28

There are both proconvulsant and anticonvulsant results for tricyclics in humans. In a case report of a patient whose seizures increased in frequency during a period of severe depression, desipramine improved both conditions.29 In contrast, another case report indicated that a child on imipramine exhibited a seizure disorder.30 Another case report showed that eight patients on conventional doses of tricyclics had elevated plasma levels of the drugs and suffered from grand mal seizures.31 In a study of 100 persons who experienced severe tricyclic antidepressant overdose, 31 had seizures during the overdose.32 A review study reported that persons on high doses of imipramine who had no predisposing factors for seizures exhibited a seizure rate of approximately 0.6–0.9%.33 Another review paper of tricyclics reported a relatively high rate of seizures (0.4 to 1–2%) at therapeutic doses.34

Two newer drugs, reboxetine and atomoxetine, which very specifically boost NE, may also affect epilepsy-related phenomena. In mice, reboxetine has both proconvulsant and anticonvulsant effects on flurothyl-induced seizures.9 A study of persons with comorbid temporal lobe epilepsy and major depression found that treatment with reboxetine did not increase the frequency or severity of seizures.35 Two epidemiological studies, put forth by the manufacturer of atomoxetine, concluded that this drug does not increase the risk of seizures in persons being treated for attention deficit hyperactivity disorder (ADHD).36, 37 In a case report, a woman who overdosed on a very high dose of atomoxetine, presented in the emergency room with a tonic-clonic seizure.38

As described above, NE boosting drugs can have both proconvulsant and anticonvulsant effects in various organisms under different experimental conditions. In rodents, more studies showed proconvulsant effects18, 19, 20, 21, 24, 25 than anticonvulsant ones,22, 23, 26, 27 or both effects in the same study.2, 9 Human case reports were more frequently proconvulsant30, 31, 38 than anticonvulsant,29 although perhaps there is a bias toward reporting more proconvulsant incidents, including those related to overdoses. In sum, these data support both the NE proconvulsant and anticonvulsant hypotheses.

3.2. Clonidine and other alpha 2 adrenergic agonists 

Animal and human studies show that clonidine and other alpha 2 adrenergic agonist drugs can affect convulsions. These drugs may have opposing effects on noradrenergic transmission, both decreasing presynaptic NE release via alpha 2 autoreceptors and activating postsynaptic alpha 2 receptors.39 Because of this, these drugs may decrease noradrenergic transmission by decreasing NE release, or increase such transmission by acting as a postsynaptic agonist. These two possibilities will be addressed further in Section 4.

There are both proconvulsant and anticonvulsant results for clonidine in the rat. In a study of audiogenic seizures, clonidine at high doses was anticonvulsant, whereas at low doses (which are thought to be more presynaptic) it was proconvulsant.40 In rats implanted with chronic electrodes, clonidine and the alpha 2 agonist guanfacine prolonged EEG paroxysms, as did the alpha 1 antagonist drug, prazosin.41 For quinolinic acid-induced convulsions, clonidine was proconvulsant at low doses and anticonvulsant at higher doses.42

For allylglycine-induced seizures in the rat, clonidine had an anticonvulsant effect.43 That result, coupled with an anticonvulsant effect of prazosin in the same study, led the authors to conclude that decreased noradrenergic transmission has an anticonvulsant effect in this animal model.43 In another study, clonidine and four other alpha 2 agonists had an anticonvulsant effect on pentylenetetrazol (PTZ)-induced convulsions.44 Another finding is that a subthreshold dose of clonidine, when combined with the drug di-n-propylacetate (DPA), had an anticonvulsant effect on PTZ-induced convulsions.45 In a hippocampal slice preparation, clonidine and other alpha receptor agonists were anticonvulsant, whereas various beta receptor agonists were proconvulsant.46 Depletion of NE with the drug AMPT potentiated kainic acid-induced epileptic symptoms, and the effect was antagonized by clonidine.47

In the quaking mouse model of epilepsy, clonidine and prazosin had a proconvulsant effect on handling-induced convulsions.48 Regarding anticonvulsant effects of clonidine in the mouse, a study of this drug and two other alpha 2 agonists found that these drugs reduce the severity of audiogenic seizures.49 In another study, clonidine had an anticonvulsant effect on metaldehyde-induced seizures.50 Clonidine protected against imipramine-induced seizures, as did prazosin and AMPT, suggesting that decreasing noradrenergic transmission is anticonvulsant in this animal model.51 In a related study, a number of noradrenergic drugs modulated strychnine-induced seizures, with clonidine being anticonvulsant, and the authors conclude that increasing noradrenergic transmission is proconvulsant here.52

There do not appear to be many studies of the effects of clonidine on human epilepsy. In a study of 14 epileptic patients, premedication with clonidine increased focal epileptic discharges in nine, as measured with magnetoencephalography (MEG).53 In another MEG study of epileptic patients, about 67% showed increased spike activity with clonidine administration.54

The above data show both proconvulsant and anticonvulsant effects for clonidine and other alpha 2 agonists in animal models. In rodents, fewer alpha 2 agonist studies showed proconvulsant effects41, 48 than anticonvulsant effects,43, 44, 45, 46, 47, 49, 50, 51, 52 and some showed both,40, 42 which may depend on dose. Two human studies showed proconvulsant effects.53, 54 As mentioned above, clonidine and other alpha 2 agonists may either be increasing or decreasing noradrenergic transmission, so these data do not strongly indicate whether NE is proconvulsant or anticonvulsant, but at least suggest that NE affects convulsions and may have both proconvulsant and anticonvulsant properties under various conditions.

3.3. Prazosin and other alpha receptor studies 

Studies of the alpha 1 antagonist drug, prazosin, related drugs, and binding studies of the alpha 1 receptor indicate a role for this receptor in epilepsy. In a study of anesthetized rats, prazosin blocked the suppression of penicillin-induced focal epileptiform activity produced by locus coeruleus stimulation.55 In other words, prazosin was proconvulsant in this model.55 In a mouse model of electroshock seizures, the alpha 1 agonist St 587 and the beta agonist isoprenaline were both proconvulsant.56 In another study, St 587 had no effects on the thresholds for electroshock and PTZ-induced seizures in mice and rats, but was anticonvulsant in kindled rats and epileptic gerbils.57 A binding study revealed that there may be fewer alpha 1 recognition sites in the genetically epilepsy prone rat.58 The age related susceptibility of the DBA/2J strain of mice to audiogenic seizures may be related to a reduced number of alpha 1 binding sites, rather than to alpha 2 or beta adrenoceptor binding sites.59 Transgenic mice that overexpress the alpha 1b receptor exhibit increased in vivo spontaneous interictal epileptogenicity and EEG/behavioral seizures.60 Moreover, alpha 1b knockout mice are markedly resistant to chemoconvulsants.61 In human patients with epilepsy, there is reduced alpha 1 receptor density, as measured by labeled prazosin binding, at sites in epileptic foci.62

The above rodent data on prazosin show a proconvulsant effect,55 whereas the alpha 1 agonist St 587 was proconvulsant in one study56 and anticonvulsant in another.57 These data suggest both proconvulsant and anticonvulsant affects for NE. The alpha 1 receptor data do not strongly suggest whether NE is proconvulsant or anticonvulsant, as reductions in receptor density are associated with convulsions58, 59 or protection against convulsions,61 whereas overexpression is proconvulsant.60

3.4. Propranolol and other beta receptor drug studies 

Propranolol is a non-selective beta adrenoceptor antagonist drug, meaning it blocks both beta 1 and beta 2 receptors, and it appears to affect epilepsy. In the rat, propranolol blocked the reduction of penicillin-induced hippocampal spiking produced by locus coeruleus stimulation.63 In other words, propranolol was proconvulsant in this model.63 Regarding anticonvulsant results in the rat, intracerebroventricular administration of propranolol and another beta blocker, timolol, was anticonvulsant in a PTZ-induced model of convulsions.64 In the same study, various beta 1 antagonists were only weakly anticonvulsant, leading the authors to conclude that deactivation of beta 2 receptors is anticonvulsant.64 Pretreatment with propranolol inhibited isoniazid-induced convulsions in a dose dependent manner.65 In a study of lidocaine-induced convulsions in awake rats, propranolol increased seizure thresholds.66

In the mouse, propranolol (and reserpine) reduced latency for PTZ-induced seizures.67 Propranolol also antagonized strychnine-induced seizures.68 Audiogenic seizure prone DBA/2 mice had increased density of midbrain beta adrenergic receptors, compared with seizure resistant C57BL/6 mice.69 In the same study, propranolol attenuated all stages of seizure syndrome.69 Propranolol and the beta blocker pindolol exhibited significant protective effects against maximal electroshock seizures.70 Propranolol alone, and in combination with the drug nifedipine, produced an anticonvulsant effect on maximal electroshock-induced seizures.71 Propranolol was also anticonvulsant in audiogenic, tonic-clonic seizures in DBA/2 mice.72 This drug and its two enantiomers dose dependently raised the threshold for tonic electroshock seizures.73

Regarding human results with this drug: in two infants with involuntary movements of polymyoclonia and opsoclonus, propranolol produced marked improvement in both children.74 In 12 patients with chronically unstable generalized epilepsy, treatment with propranolol produced a significant reduction in epileptic manifestations.75

In the above rodent data, propranolol more frequently had anticonvulsant properties64, 65, 66, 68, 69, 70, 71, 72, 73 than proconvulsant ones,63, 67 suggesting a proconvulsant role for NE since propranolol blocks noradrenergic transmission. Two human studies also support the NE proconvulsant hypothesis, since propranolol was anticonvulsant in these studies.74, 75

An additional point of evidence regarding a proconvulsant role for NE in rodents comprises the mutant “tottering” mouse.76 This mouse has hyperinnervation of various brain structures (such as hippocampus and cerebellum) by axons of the locus coeruleus, and concomitant elevated levels of NE in these structures, while exhibiting spontaneous spike-wave and focal motor seizures.76 Besides the NE increase in these mice, other pharmacological parameters are normal, such as tyrosine hydroxylase activity, NE turnover, serotonin content, and choline acetyltransferase activity.77 The proconvulsant phenotype of these mice can be mitigated by selective lesions of central noradrenergic axons early in development.78

3.5. Pheochromocytoma 

Pheochromocytoma is a rare cancer of the adrenal glands that can boost NE levels systemically. Hypertension, which is often present in pheochromocytoma, may make the blood–brain barrier permeable to NE, thereby allowing NE released by the adrenal glands to penetrate the brain.79 There are several reports of this cancer being proconvulsant. A patient with complex partial seizures had a cluster of symptoms suggestive of pheochromocytoma.80 A child with a malignant form of pheochromocytoma showed central nervous system symptoms imitating epilepsy.81 In another case report, a child presented with seizures and a hypertensive crisis, and was found to have multiple extra-adrenal pheochromocytomas.82 A young man developed seizures along with hypertension and other symptoms; he was diagnosed with pheochromocytoma and adrenalectomy resulted in complete recovery.83 These data support the NE proconvulsant hypothesis.

3.6. Bipolar disorder, hypertension, and obesity 

Evidence that NE is elevated in persons with bipolar disorder dates back to the catecholamine hypothesis of mood disorders, put forth by the late Schildkraut.84 There is also blood measure evidence that brain NE is elevated during periods of mania or hypomania,85 where changes in plasma MHPG (an NE metabolite) may reflect changes in central NE. The rate of both unipolar depression and bipolar disorder in people with epilepsy appears to be higher than in the general population.86 In a survey of 127,800 adults in the United States, bipolar symptoms were present in 12.2% of persons with epilepsy, and the two illnesses were more frequently comorbid than bipolar disorder was with migraine headaches, asthma, or diabetes mellitus.87 Bipolar disorder was also 6.6 times more common in persons with epilepsy than in healthy subjects.87 In a study of 143 adult outpatients with epilepsy, 11.8% had bipolar disorder as well.88 In another study of 117 adult outpatients, 14.5% met DSM-IV criteria for having manic or hypomanic episodes.89 There is a case report of a patient who presented with bipolar mania and photoconvulsive epilepsy, who was treated successfully with carbamazepine.90 Epilepsy and bipolar disorder may also share biochemical and pathophysiological commonalities, including kindling.91 In patients with comorbid bipolar disorder and epilepsy, anticonvulsants often treat both disorders simultaneously.92 In general, anticonvulsants are commonly used to treat bipolar disorder.93 The above data on bipolar disorder are consistent with the NE proconvulsant hypothesis, without supporting the anticonvulsant hypothesis.

Persons with hypertension may in some cases have elevated levels of plasma NE,94 and drugs that lower NE, such as clonidine, reduce blood pressure.95 There is evidence that both plasma and CSF NE are elevated in hypertensives compared to normotensives.96, 97 Even persons with borderline hypertension may have elevated plasma and CSF NE.98 In a case–control study of subjects 55 years or older, severe uncontrolled hypertension increased the risk of unprovoked seizures.99 In a large case–control study, a variety of vascular determinants, including hypertension, were associated with lifetime epilepsy and late-onset epilepsy.100 These data on hypertension are consistent with the NE proconvulsant hypothesis.

In humans, excessive body weight is associated with adrenoceptor polymorphisms and elevated blood NE.101 A strain of genetically obese mice (called OBOB) has higher levels of hypothalamic and telencephalic NE than lean littermates.102, 103 In rats, chronic infusion of NE into the ventromedial hypothalamus induces obesity.104 These data suggest that there is elevated central NE in some cases of obesity. There are high rates of obesity in persons with epilepsy, with one study of 8057 adults reporting a 34.1% rate of obesity, versus a 23.7% rate in persons without epilepsy.105 Children with newly diagnosed untreated epilepsy had higher body mass index compared to healthy controls; 38.6% of the epilepsy cohort were overweight or obese.106 Another study reports that poor fitness and obesity are common in persons with epilepsy.107 However, teens with epilepsy may simply participate in fewer sports activities than controls, so lack of exercise may result in them being overweight.108 These data on obesity are consistent with the NE proconvulsant hypothesis.

3.7. Psychological stress 

Psychological stressors can produce marked release of NE in the bloodstream (and the brain) as part of the body's sympathetic “fight or flight” response. Psychological stress can have an anticonvulsant effect, which has been demonstrated in mice109 and rats.110 A study of persons with epilepsy who were evacuees from a natural disaster, versus control persons with epilepsy, found that this stressor produced a small increase in the number of seizures.111 A related point is that having seizures is itself stressful, and this may lead to various pathophysiological changes that trigger physical illnesses,112 which may feed back on the epilepsy itself. These data support both the NE proconvulsant and anticonvulsant hypotheses.

An additional line of evidence that is potentially relevant to the NE proconvulsant hypothesis comprises data directly relating CSF NE with convulsions. As noted above, a caveat is that having epilepsy is stressful for persons, and this stressor may feedback on the NE system and thereby increase NE levels.112, 113 A second caveat is that the process of measuring CSF NE levels, typically through a spinal tap, is a potentially stressful surgical procedure that may also feedback on the NE system and increase NE levels. A study of 15 persons with epilepsy and 75 controls found higher CSF levels of NE in epileptics.114 However, another study found similar CSF concentration of the NE metabolite, MHPG, between persons with partial complex seizures and neurologic controls.115 Following secondarily generalized tonic-clonic seizures, CSF NE concentration was significantly higher than interictal concentration,116 suggesting that NE may either increase before or just after seizures.

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4. Discussion 

The evidence reviewed in this paper supports the hypothesis that NE is proconvulsant under some conditions. Much of the evidence also supports the more well-established hypothesis that NE has anticonvulsant properties (see Table 1). What follows is a brief discussion of the implications of the reviewed data, and a few ideas related to NE and epilepsy.

Table 1. Summary of data. The presence or absence of one or more studies cited in this review that supports the given question is noted by a “Yes” or “No”. This table only includes data for the given classes of drugs themselves, rather than related receptor studies noted in the text. The evidence for alpha 2 agonists is inconclusive because they may either be increasing or decreasing noradrenergic transmission.
ProconvulsantAnticonvulsantSupports NE proconvulsant hypothesisSupports NE anticonvulsant hypothesis
NE boosting antidepressantsYesYesYesYes
Alpha 2 agonistsYesYes??
Alpha 1 antagonistsYesYesYesYes
Beta blockersYesYesYesYes
PheochromocytomaYesNoYesNo
Bipolar disorderYesNoYesNo
HypertensionYesNoYesNo
ObesityYesNoYesNo
Psychological stressYesYesYesYes

The tricyclic antidepressant studies, as well as studies of reboxetine and atomoxetine, may provide a direct test of NE convulsive hypotheses since these drugs appear to principally boost NE.15, 16, 17 Many of the reviewed tricyclic studies indeed support the NE proconvulsant hypothesis, both in animals and humans. Studies of the drug clonidine and other alpha 2 adrenergic agonists provide a far less direct test of the proconvulsant hypothesis, since these drugs may both decrease presynaptic release of NE and stimulate postsynaptic alpha 2 receptors, and the relative importance of the two potentially opposing effects may differ in various animal models and in humans. Ref. 5 appears to resolve the controversy in mice, where clonidine is reported have a proconvulsant effect based on a decrease in autoreceptor-mediated release of NE. Nonetheless, the safe conclusion from the clonidine data is that NE has convulsive effects, but whether NE is proconvulsant or anticonvulsant in all species may not be resolved by these data. On the other hand, when the clonidine data are combined with data from other noradrenergic drugs (such as prazosin) in the same study,41, 43, 51 these data can shed light on the convulsive hypotheses, since the other drugs may reveal which of clonidine's two mechanisms is more prominent in the given study. The prazosin and propranolol data provide a more direct test of the NE convulsive hypotheses, since these drugs block noradrenergic transmission through particular adrenoceptors. Many of the results for these two drugs are anticonvulsant, which when combined with the tricyclic data, strengthen the NE proconvulsant hypothesis. It should be noted that in cases where NE may be proconvulsant, the effect need not be mediated through all subtypes of adrenoceptors. In other words, some receptor subtypes could still be anticonvulsant when activated by NE or a drug.

The results for pheochromocytoma being associated with seizures are interesting but caution should be noted since these are case reports. The association of bipolar disorder, hypertension, and obesity with epilepsy is also promising for the NE proconvulsant hypothesis. However, the interpretation of these results, for hypertension and obesity (and pheochromocytoma), is dependent on whether NE is elevated in the brain under these conditions. Elevated blood NE may result in elevated brain NE,79 although this is not necessarily the case. Pheochromocytoma, bipolar disorder, hypertension, and obesity may be associated with other phenomena that increase the rate of epilepsy, but increased NE is one of these candidate phenomena. The potential relationship between psychological stress and epilepsy merits further investigation.

It appears that NE has general proconvulsant properties that are not specific to a particular type of epilepsy, brain region, convulsant agent, treatment duration, or species. For each of these five entities there are examples of NE's non-specificity. For example, regarding type of epilepsy, several tricyclics enhanced spontaneous absence-like seizures in rats,20 whereas propranolol was anticonvulsant in audiogenic, tonic-clonic seizures in DBA/2 mice.72 The above studies also showed proconvulsant effects of NE on different brain regions. For example, a study in anesthetized cats found that various tricyclics produced epileptiform pathology in neocortex, hippocampus, and brainstem.28 In addition, a large number of the above studies showed that the proconvulsant effects of NE are not limited to a particular convulsant agent (e.g., lidocaine or PTZ). For example, therapeutic doses of desipramine in mice were proconvulsant in a model of lidocaine-induced seizures,25 and propranolol and another beta blocker, timolol, were anticonvulsant in a PTZ-induced model of convulsions.64 In addition, the proconvulsant properties of NE were evident both upon acute28 and chronic19 drug administration. Finally, proconvulsant results for NE were present in a number of species described in this paper, including mice, rats, cats, and humans. This body of evidence is consistent with the hypothesis that NE has general proconvulsant properties.

The mechanism of action by which NE may achieve its proconvulsant effects, or its anticonvulsant ones, remains unclear. Since adrenoceptors are G protein-coupled receptors that produce changes in intracellular second messenger processes, such as the level of cyclic AMP (cAMP), as a result of binding to NE, one avenue of inquiry into the convulsive effects of NE would be pharmacological or genetic manipulation of relevant second messenger processes in brain slice preparations. One possibility is that NE produces increases in cellular membrane potential as a result of binding to its receptors, consistent with the idea that NE increases general excitability of neurons. However, this hypothesis would not necessarily predict that all neurons in noradrenergic circuits should be excited by NE, since inhibitory interneurons might show decreases in membrane potential. Another possibility is that NE has no direct effects on convulsions through changes in membrane potential, but instead some other second messenger process facilitates convulsions originating in those neurons. A third possibility is that NE has no direct effect on convulsions through membrane potential or other second messenger processes in neurons bearing adrenoceptors, but instead these cells participate in circuits that facilitate convulsions in non-adrenergic receptor bearing cells.

How might one go about testing the NE proconvulsant hypothesis itself, to a greater degree than it has already been tested? As reviewed in this paper, there is already a large body of evidence in support of the hypothesis. However, continued inquiry into the hypothesis may not only better establish its validity, but also provide more information about the circumstances in which NE plays a proconvulsant role. Since noradrenergic drugs are not considered a first-line treatment for epilepsy in most persons, perhaps double blind, placebo controlled studies could be undertaken that add noradrenergic drugs, such as desipramine, clonidine, or propranolol, onto existing anticonvulsant drug regimens. Epidemiological studies of seizure rates in large numbers of persons who have taken noradrenergic drugs (especially when these are the only drugs being taken), including data on persons with no history of seizures, would also shed further light on the hypothesis.33, 34 Regarding animal models, perhaps more electrophysiological studies could be conducted that apply NE directly to brain slices and measure effects on convulsions, which would constitute a more direct test of the hypothesis than administration of drugs that manipulate NE or its receptors, since these drugs may have additional effects on other neurotransmitter systems or cellular processes. Alteration of noradrenergic genes in mice, including both knock-in and knockout manipulations, would also provide additional testing of the NE convulsive hypotheses, especially as we come to understand murine noradrenergic genes in greater detail.3, 4, 5, 61

Regarding the potentially proconvulsant role of NE in some cases of epilepsy, an analogy can be drawn with the field of pharmaceutical drug treatment of asthma. Long acting beta agonist (LABA) drugs, which activate beta adrenoceptors, have been a standard anti-inflammatory treatment of asthma for many years. However, a recent seminal paper in that field117 showed that one LABA, salmeterol, can actually increase respiratory-related mortality. Perhaps a similar situation exists for epilepsy, wherein increasing noradrenergic transmission may in some cases be beneficial, but may also in certain situations be harmful (though not necessarily lethal).

One concept that may unify the NE proconvulsant and anticonvulsant hypotheses is that perhaps either too high or too low an extracellular concentration of this neurotransmitter is proconvulsant. In other words, a mid-range brain concentration of NE may be most healthy. For example, when raising the level of NE with a tricyclic antidepressant is proconvulsant in a given animal or human, perhaps the endogenous level of NE was already at a mid-range value. Or, when raising NE with a tricyclic is anticonvulsant, perhaps the endogenous level of NE was too low. A related idea is that changes in the concentration of NE, induced by pharmaceutical drugs for example, may have proconvulsant or anticonvulsant effects under different conditions in various organisms. If NE is indeed proconvulsant in some cases of epilepsy, treatment with noradrenergic transmission decreasing pharmaceutical drugs, such as propranolol and perhaps clonidine, may be indicated in those cases.

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Conflict of interest 

The author has no conflict of interest to disclose.

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Acknowledgements 

I am currently employed by and receive income from the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Rockville, Maryland, USA), through its Intramural Research Trainee Awardee (IRTA) program. The work was conceived while I was employed in the Johns Hopkins University, Department of Neuroscience, and it was not supported by a grant.

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References 

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PII: S1059-1311(10)00086-5

doi:10.1016/j.seizure.2010.04.011

Seizure: European Journal of Epilepsy
Volume 19, Issue 6 , Pages 311-318, July 2010

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