International Psychogeriatrics, Vol. 13, No. 4, 2001, p p . 461-464 02001 International Psychogeriatric Association
Butyrylcholinesterase and Cognitive Function SULTAN DARVESH, CHRISMACKNIGHT, AND KENNETH ROCKWOOD ABSTRACT. Butyrylcholinesterase (J3uChE) is expressed in brain structures involved in cognition, but the effect of selective BuChE inhibitors on human cognitive function is unknown. We report a patient whose cognitive function deteriorated following a reduction and improved following reinstitution of ethopropazine, a selective BuChE inhibitor. We suggest that, because neurons expressing BuChE may be involved in cognition, there is merit to further evaluation of selective BuChE inhibitors in treating cognitive dysfunction. KEYWORDS: Cholinesterase; ethopropazine; Alzheimer
2000). We report an effect on cognition of the BuChE inhibitor ethopropazine, which supports a role of BuChE-expressing neurons in cognitive function.
Cholinergic neurotransmission plays an important role in human cognitive functions (Francis et al., 1999). Acetylchol i n e s t e r a s e (AChE) c a t a l y z e s t h e hydrolysis of the neurotransmitter acetylcholine. In diseases with cholinergic dysfunction, inhibitors of cholinesterases have been shown to improve cognitive function (Giacobini, 2000). Although much attention on cognition has focused on AChE and its inhibitors, the importance to cognition of the related enzyme butyrylcholinesterase (BuChE) is less well understood (Giacobini, 2000; Greig et al., 1998). The distinctive distribution of BuChE in the central nervous system draws attention to its p o t e n t i a l i m p o r t a n c e in cognition (Darvesh et al., 1996, 1998; Mesulam, 2000). Most of the drugs used in the treatment of Alzheimer’s disease inhibit not only AChE but also BuChE (Giacobini,
A41-year-old man with a history of schizophrenia presented for investigation of memory impairment. He described impaired concentration and worsening memory over 4 months (e.g., misplacing items, forgetting details and, at times, important events), which were compromising his occupational function to the extent that he now needed to make lists of tasks at his workplace. He related the onset of these symptoms to a reduction in the dose of ethopropazine, which had been prescribed to control extrapyramidal side effects of the neuroleptic chlorpromazine.
From the Department of Medicine, Divisions of Neurology (S. Darvesh, MD, PhD) and Geriatric Medicine (S. Darvesh; C. MacKnight, MD; and K. Rockwood, MD), Dalhousie University, Halifax, Nova Scotia, Canada.
Offprints.Requests for offprints should be directed to Dr. Sultan Darvesh, QEII Health Sciences Centre, Room 1308,Camp Hill Veterans Memorial, 5955 Veterans’ Memorial Lane, Halifax, Nova Scotia, B3H 2E1 Canada. email:
[email protected]
CASE REPORT
46 1
S. Darvesh et al.
462
Four months earlier, his ethopropazine dose had been decreased from 100 mg three times a day to 50 mg twice a day. His schizophrenia symptoms remained stable, with occasional visual and auditory hallucinations and some delusions of thought insertion and of grandeur but no paranoia or depression. His past history was remarkable for a remote motor vehicle accident, leading t o a head injury and splenectomy, elevated cholesterol level, and irritable bowel syndrome. In addition to ethopropazine, he took chlorpromazine 100 mg twice a day, nizatidine 150 mg twice daily, lorazepam 1 mg at bedtime, and two puffs of salbutamol three times daily, as well as pinaverium and loperamide for his bowel symptoms. He had a Grade 10 education. Results of the general and neurological examinations were unremarkable. His Mini-Mental State Examination (MMSE) score was 27/30, with 1 point lost each for the date, recall, and repetition. His clock drawing was abnormal (Figure 1:Panel A). He was able to draw a circle and place some of the numbers, but when asked to place the hands at 10 after 11, he was able to place a mark only at 11.His biochemical profile, hemogram, computed tomographic scan of the brain, and electroencephalogram were all within normal limits. He did not wish to undergo a detailed neuropsychological assessment. The dose of ethopropazine was reinstituted at 100 mg three times a day. On review 2 months later, his symptoms had improved. His psychiatrist, in the interval, had replaced t h e chlorpromazine with haloperidol 2.5 mg three times a day. His clock drawing had improved, but the MMSE score was 22/30. Six months later h e continued t o report improvement. His MMSE score was 26/30 and his clock drawing was normal. In the International Psychogeriatrics, 13(4), December 2001
6 Panel A
Panel B Figure 1. Clocks drawn by the patient before (Panel A) and after (Panel B) reinstitution of higher dose of ethopropazine.
interval, his neuroleptic h a d b e e n changed to risperidone 2.5 mg twice a day. Three months following this (9
463
Butyrylcholinesterase and Cognitive Function
months after presentation), h e continued t o report improvement compared to baseline. The MMSE score was 27/30. The clock drawing remained improved compared with baseline, although he now demonstrated a pattern consistent with frontal systems dysfunction (Figure 1: Panel B).
DISCUSSION In this patient, a reduction in the dose of ethopropazine was associated with symptomatic and clinical worsening of cognition. Reinstitution of a higher dose of ethopropazine was associated with sustained improvement, notwithstanding interval changes in the choice and dosing of a concomitant neuroleptic medication. Ethopropazine is a phenothiazine derivative used to treat both spontaneous (Fahn, 1987) and drug-induced extrapyramidal symptoms (Chouinard et al., 1979). It has been suggested that ethopropazine is effective in treatingextrapyramidal side effects because of its anticholinergic properties, although it is not as potent as other anticholinergic agents at muscarinic (Katayama et al., 1990) or nicotinic receptors (Gao et al., 1998). In this patient, although the treating psychiatrist had elected to modify the neuroleptic treatment, the patient’s symptoms of schizophrenia remained stable.Although replacing chlorpromazine with haloperido1 may have had an impact on his cognition,we saw astriking temporal relationship between a reduction in the ethopropazine dose and deterioration of cognitive function. Equally,subsequent improvement was witnessed when a higher dose of ethopropazine was reinstituted. Because of the anticholinergicproperties of ethopropazine at both muscarinic and nicotinic receptors
(Gao et al., 1998; Katayama et al., 1990), increasing the dose of ethopropazine should have led to deterioration of cognitive functions. In this case, however, increasing the dose of ethopropazine had an opposite effect. We suggest that this was due to its properties as a potent and specific inhibitor of the enzyme BuChE (Silver, 1974). BuChE is expressed in distinct p o p ulations of neurons in the human brain, including amygdala, hippocampal formation, and other forebrain structures such as the thalamus (Darvesh et al., 1996,1998; Mesulam, 2000). It has been shown that in patients with schizophrenia there is a significant loss of neurons, particularly in the mediodorsal nucleus of the thalamus (pop ken et al., 2000). In the normal brain, a substantial number of neurons in the m e diodorsal nucleus of the thalamus express BuChE (Darvesh et al., 1996). Taken together, we suggest that the improvement in this patient’s cognitive function is consistent with the effect of ethopropazine on inhibition of BuChE in these structures. Given these data, and the suggestion that drugs that inhibit both AChE and BuChE improve cognitive function (Giacobini, 2000; Greig et al., 1998), we believe that there is merit in further evaluation of selective BuChE inhibitors in treating cognitive dysfunction.
REFERENCES Chouinard, G., Annable, L., Ross-Chouinard, A., & Kropsky, M. L. (1979). Ethopropazine and benztropine in neurolepticinduced parkinsonism. Journal of Clinical Psychiatry, 40, 147-152. Darvesh, S., Grantham, D. L., &Hopkins, D. A. (1998). Butyrylcholinesterase in normal human amygdala and hippocampal formation. Journal of ComparativeNeurology, 393, 374-390.
464
Darvesh, S., Grantham, D., & Hopkins, D. A. (1996). Distribution of butyrylcholinesterase in normal human forebrain. Neuroscience Abstracts, 22, 20 1. Fahn, S. (1987). Systemic therapy of dystonia. CanadianJournal of Neurological Sciences, 14,528-532. Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. (1999). The cholinergic hypothesis of Alzheimer’s disease: A review of progress. Journal of Neurology, Neurosurgery and Psychiatry, 66, 137-147. Gao, Z. C., Liu, B. Y., Cui, W. Y., Li, L. J., Fan, Q. H., et al. (1998). Anti-nicotinic properties of anticholinergic antiparkinson drugs. Journal of Pharmacy and Pharmacology, 50, 1299-1305. Giacobini, E. (2000). Cholinesterase inhibitors: From calabar bean to Alzheimer therapy. In E. Giacobini (Ed.), Cholinesterases and cholinesterase inhibitors (pp. 181-226). London: Martin Dunitz. Greig,N. H., Lahiri, D. K.,Soncrant, T.T., Utsuki, T., Yu, 0. S., et al. (1998). Novel, selective butyrylcholinesterase (BuChE) inhibitors for the treatment of Alzheimer’s disease (AD). Neuroscience Abstracts, 24, 728.
International Psychogeriatrics, 13(4), December 2001
S. Daruesh et al.
Katayama, S., Ishizaki, F., Yamamura, Y., Khoriyama, T., &Kito, S. (1990). Effects of anticholinergic antiparkinsonian drugs on binding of muscarinic receptor subtypes in rat brain. Research Communications in Chemical Pathology and Pharmacology, 69, 261-270. Mesulam, M. (2000). Neuroanatomy of cholinesterases in the normal human brain and Alzheimer’s disease. In E. Giacobini (Ed.), Cholinesterases and cholinesterase inhibitors (pp. 121-137). London: Martin Dunitz. Popken, G. J., Bunney, W. E., Potkin, S. G., & Jones, E. G. (2000). Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proceedings of the National Academy of Sciences USA, 97, 92769280. Silver, A. (1974). The biology of cholinesterases. Amsterdam: Elsevier.
Acknowledgments. Grants from the QE I1 Health Sciences Centre Research Fund, and the New Brunswick Heart and Stroke Foundation during preparation of this manuscript.
