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Motor neuron disease

The motor neurone diseases (MND) are a group of progressive neurological disorders that destroy motor neurons, the cells that control voluntary muscle activity such as speaking, walking, breathing, and swallowing. Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), progressive bulbar palsy (PBP) and primary lateral sclerosis (PLS) are all motor neurone diseases. more...

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MND is the term often used internationally while ALS is often used in the United States (where it is also known as Lou Gehrig's disease, after the legendary baseball player) to cover all forms of MND. It was first described by Jean-Martin Charcot, a French neurologist, in 1869 and in France the disease is therefore known as Maladie de Charcot (Charcot's disease).

Signs and symptoms

Characteristic symptoms of MND include gradual weakening, wasting away, and uncontrollable twitching of the muscles; spasticity or stiffness in the arms and legs; and overactive tendon reflexes. Sensation, intellect, memory, and personality are not affected in MND. In some types of MND, such as ALS, muscle weakness is progressive and eventually leads to death when the muscles that control breathing no longer work. Other types of MND progress slowly and last over a lifetime.

In adults, symptoms usually appear after age forty, and may be similar to those of other diseases, making diagnosis difficult. In children, particularly in inherited forms of the disease, symptoms are present from birth.


The diagnosis of ALS is established based on the history of the patient and the findings on neurological examination. There is no diagnostic test for ALS. Electromyography (EMG) examination are useful to demonstrate the diffuse loss of motor neurones innervating muscles of extremities, face and abdomen and to rule out other disorders that may mimic ALS, but interpretation of the result is not necessarily straight forward. A set of diagnostic criteria called the El Escorial criteria have been defined by the World Federation of Neurologists and are widely used by neurologists and ALS researchers.

Clinically, upper motor neuron damage signs (such as spasticity, brisk reflexes and Babinski signs) can be found, while the lower motor neurones demonstrate weakness and muscle atrophy. Weakness of bulbar musculature can also be seen (difficulty breathing, swallowing, coughing, or speaking).

Neuroimaging examinations are usually performed to rule out alternative causes, such as a mass lesion of upper parts of spinal cord



Nonhereditary (also called sporadic) MND are caused by unknown factors. Nonhereditary MND include ALS, progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, progressive muscular atrophy, and post-polio syndrome. There are no specific tests to diagnose the MND.

About 90% of cases of MND are "sporadic", meaning that the patient has no family history of ALS and the case appears to have occurred sporadically in the community. The cause of sporadic ALS is unknown, though genetic factors are suspected to be important in determining an individual's susceptibility to disease. There is weak evidence to the suggestion that the onset can be triggered by a viral infection, but this is not widely believed in the ALS research community. The remaining 10% of cases are "familial", defined as more than one case of ALS in a family. Familial ALS is genetic in aetiology and the following genes are known to be linked to ALS: Cu/Zn superoxide dismutase SOD1, ALS2, NEFH(a small number of cases), senataxin (SETX) and vesicle associated protein B (VAPB).


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Temocapril prevents motor neuron damage and upregulation of cyclooxygenase-II in glutamate-induced neurotoxicity
From Neurological Research, 4/1/03 by Iwasaki, Yasuo

To examine the possible neuroprotective effect of temocapril, one kind of angiotensin-converting enzyme inhibitor, against glutamate-incluced neurotoxicity, we analyzed the pharmacologie utility of temocapril in a post-natal organotypic culture model of motor neuron degeneration. Treatment with 10^sup -5^ M of glutamate resulted in a motor neuron loss and decreased activity of choline acetyltransferase (ChAT). Cotreatment of 10^sup -5^M of glutamate and temocapril revealed protective effect on motor neuron death and decreased activity of ChAT. Next we performed reverse transchption-PCR analysis for cyclooxygenase-ll (COX-II). COD-11 mKNA was upregulated in glutamate-treated culture. Cotreatment with temocapril and glutamate inhibited upregulation of COX-II. Taken together, temocapril may have therapeutic potential for diseases which associate with upregulation of COX-II, in addition to its role in glutamate excitotoxicity. [Neurol Res 2003; 25: 301-304]

Keywords: Temocapril; angiotensin-converting enzyme inhibitor; glutamate-induced neurotoxicity; cyclooxygenase-ll; neuroprotection


Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of high blood pressure and chronic heart failure1. Besides their roles as the antihypertensive drugs, ACE inhibitors have been reported to have neuroprotective action against cerebral ischemia in a rat model2"5. It has been reported that some of the ACE inhibitors attenuated cardiomyocyte apoptosis in spontaneously hypertensive rats6. Ravati ef al.7 reported that enalapril and moexipril could protect cortical cultured neurons from glutamate-induced neuronal damage. Glutamate-induced neurotoxicity is implicated in neuronal damage associated with ischemie stroke and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD)8'9. Furthermore, ACE inhibitors could have a therapeutic potential on cellular apoptosis which may play a role in the pathogenesis of neurodegenerative disorders10.

ALS is a progressive, fatal disease with muscular weakness caused by selective degeneration of upper and lower motor neurons. Etiopathogenesis of ALS remains unknown. Excitotoxicity may contribute as possible pathogenesis of ALS8. Riluzole, an inhibitor of glutamate release, is the only drug that has been approved for the treatment of ALS11. In this study, we used organotypic spinal cord culture exposed to glutamate. Accordingly, we asked whether a temocapril, which is one of the class of ACE inhibitors, could protect motor neuron death against glutamate-induced neurotoxicity.


Spinal cord organotypic culture

Organotypic spinal cord cultures were performed from lumbar spinal cords of 10-day-old Sprague-Dawley rats (Sankyo Laboratories, Tokyo, Japan). Lumbar spinal cords were removed and sliced into 10mm thick transverse sections, and one slice was placed on a milipore CM semipermeable membrane insert 30 mm in diameter in 3 ml of culture medium. Culture medium consisted of Dulbecco's modified Eagle's medium only. Antibiotics and antifungal agents were not used. Cultures were incubated at 370C in 5% CO2 and 95% air. To determine neuroprotective effects of temocapril against glutamate-induced neurotoxicity cultures were incubated with dose of 10^sup -5^ M glutamate or glutamate plus temocapril for two weeks. Culture medium alone with added temocapril, was exchanged twice weekly. We then compared two groups of motor neurons.

Prostaglandins are produced within the central nervous system by the enzymatic action of cyclooxygenase-ll (COX-II), which catalyzes the synthesis of prostaglandins from arachidonic acid. Expression of COX-II has emerged as an important determinant of cytotoxicity associated with glutamate release'2. It is important to evaluate whether temocapril possesses COX-II in glutamate-treated and glutamate plus temocapril cases, mRNA for COX-II was detected by reverse transcription-polymerase chain reaction (RT-PCR) as previously described13.

Culture morphology

The gross morphology of the cultures were monitored daily by inverted Nikon phase-contrast microscope. To count large motor neurons, cultures were treated with either 10^sup -5^ M glutamate or glutamate plus 10^sup -5^, 10^sup -6^, and 10^sup -7^ M of temocapril for two weeks. Sliced cultures were fixed with 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4 for 20 min at room temperature, then processed for cresyl violet staining. To determine the number of motor neurons in the spinal cord cultures, we counted neurons in the cultures meeting the following criteria: 1. size ( > 25 [mu]m); 2. possession of at least one thick process; and 3. location in the ventral half of the ventral gray matter14. Six to 10 culltures from each experimental group were used, and motor neurons were counted randomly by two investigators to exclude the bias of selections.

ChAT activities

The ChAT activity was determined 14 days after initial plantings. For the ChAT assay, we used incubation mixture containing 0.2 mM [1^sup -14^C]acetyl-CoA (Amersham, Toyama, Japan), 50 mM sodium phosphate buffer (pH 7.4), 300 mM NaCI, 8 mM choline chloride, 20 mM EDTA and 0.1 mM physostigmine. The homogenates (2 [mu]l) were put in microtubes, mixed, and incubated for 20 min at 37[degrees]C. The reaction was stopped by adding 5ml of 10 mM sodium phosphate buffer (pH 7.4) and the contents were transferred to scintillation vials. Then 2ml of acetonitrile containing 10mg of sodium tetraphenylborone and 1OmI of toluene scintillation mixture (0.4% DPO, 0.01% POPOP) were added to the vials. All vials were measured using a liquid scintillation counter (Aloka LC-3500, Toyama, Japan). The protein concentration was determined by a Bio-Rad protein assay kit with bovine serum albumin as standard. The enzyme activity was expressed as acetylcholine production per mg protein in 1 min. Six to 10 cultures from each experimental group were analyzed.

Statistical analysis

Results were expressed as the mean + or - SEM of a representative experiment. Statistical analysis was done using Student's f-test. The significance level was set at 0.05 for all tests.


We counted motor neurons directly in cultures that had been treated with either control medium, glutamate alone, or temocapril plus glutamate. The variance among treatment groups was highly significant, in which 10^sup -5^ M of glutamate killed a medium of 60% of motor neurons compared to untreated control. Temocapril treatment of glutamate-induced neurotoxicity cultures virtually rescued motor neuron death at any concentrations. There was no relationship between rescued neuron number and concentration of glutamate plus temocapril (Figures 1 and 2). In order to investigate biochemical activity as a surrogate marker of motor neuron survival in toxicity and neuroprotection experiments, ChAT activity dropped approximately 60% in 10^sup -5^ M of glutamate-treated cultures compared to untreated spinal cord tissues. The addition of temocapril in glutamate cultures had significant neuroprotective effects; however there was no significant relationship between doses of temocapril and its neuroprotective effect (Figure 3). Next, we sought to establish whether the COX-II expression increased glutamate-treated cultures and was reduced in temocapri!-treated cultures. COX-II mRNA was not detected in control cultures. Bands for COX-II mRNA were intense in glutamatetreated cultures. COX-II expression was completely reduced in cultures with glutamate plus temocapril (Figure 4).


In this model, we used two independent methods to show the neuroprotective action of temocapril on motor neurons. First, we counted the number of motor neurons in organotypic cultures. second, we used a biochemical assay to measure ChAT enzyme activity, since ChAT is a reliable marker mainly restricted to large motor neurons in the spinal cord. In this study we demonstrated that temocapril was protective in reducing ChAT activity, in addition to motor neuron loss against glutamate-induced neurotoxicity.

Glutamate-induced neurotoxicity can be mediated by both N-methyl-D-aspartate (NMDA) and nonNMDA glutamate receptor subtypes. Motor neurons appear to possess both NMDA and nonNMDA receptors, respectively15.

Glutamate may induce various neurotoxic cellular processes, such as formation of oxygen radicals or calcium release.

Ravati et al.7 reported that both enalapril and moexipril are ACE inhibitors, and were protective against glutamate-induced damage in primary cultures from chick embryo telencephalons. In their results, both enalapril and moexipril protected cortical neuron against glutamate-induced neurotoxicity in a similar way. However, they did not measure the ChAT activity. In our results, temocapril prevented the loss of motor neurons following glutamate exposure, in addition to maintaining the ChAT activity. The mechanism for neuroprotection by temocapril is not yet known. In the glutamate toxicity model, enalapril and moexipril possess the radical scavenging properties7. An increased release of excitatory amino acids can be observed in the presence of oxygen free radicals, indicating that reactive oxygen species reinforce the deleterious cascade of excitotoxic damage16. It has been reported that ACE inhibitors have protective effects in myocardial cells due to their ability to exert radical scavenging activities17'18.

Enalapril and Captopril were able to enhance antioxidant defences by upregulation of Superoxide dismutase or glutathione peroxidase19.

Cyclooxygenase (COX)-I and COX-II are enzymes, in which they oxidize arachidonic acid to prostaglandin endoperoxidase. In brain, COX-II has emerged as an important determinant of cytotoxicity associated with inflammation12. COX-II expression is upregulated in several neurological diseases, including stroke, AD and seizure20.

In our results the band for COX-II mRNA was intense in glutamate-treated cultures, and expression of COX-II mRNA was very weak in glutamate plus temocapril cultures.

Our results indicate that temocapril prevents the motor neuron death and upregulation of COX-II in glutamate-induced neurotoxicity.

There is a close relationship between COX-II reaction products and glutamate-mediated neurotoxicity21. ALS is a fatal disorder characterized pathologically by selective loss of motor neurons, and clinically by muscular weakness and atrophy leading to death 3-5 years after the onset.

In ALS, several abnormalities in glutamate metabolism have been reported15, which presumably could increase intracellular glutamate and calcium leading to neuronal death.

Recently, increased expression of COX-II in ALS spinal cord has also been reported22'23. COX-II inhibition seems an attractive therapeutic strategy for diseases associated with glutamate excitotoxicity.

Beside reduction of blood pressure, temocapril may have therapeutic potentials in disorders associated with glutamate induced toxicity.


Compound Temocapril (a hundred-purity) was a gift from Sankyo Co. (Tokyo, Japan).


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8 Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurological disorders. N Engl J Med 1994; 330: 613-622

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11 Lacomblez L, Bensimon G, Leigh PN, Cuilletg P, Meininger V. Dose-ranging study of ruluzole in amyotrophic lateral sclerosis. Lancet 1996; 347: 1425-1431

12 O'Banion MK. Cyclooxygenase-2: Molecular biology, pharmacology, and neurobiology. Crit Rev Neurobio! 1999; 13: 45-82

13 Nogawa S, Zhang F, Ross ME, ladecola C. Cyclo-oxygenase-2 gene expression in neurons contributes to ischemie brain damage. I Neurose/ 1997; 17: 2746-2755

14 Bilak MM, Corse AM, Bilak SR, Lehar M, Tombran-Tink J, Kuncl RW. Pigment epitheliumn-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J Neuropathol Exp Neurol 1999; 58: 719-728

15 Shaw PJ. Excitotoxicity and motor neuron disease: A review of the evidence. J Neurol Sd 1984; 124(Suppl.): 6-13

16 Pellegrini-Giampietro DE, Cherici G, Alesiani M, Carla V, Moroni F. Excitatory amino acid release from rat hippocampal slices as a consequence of free radical formation. J Neurochem 1998; 51: 1960-1963

17 Anderson B, Khaper N, Dhalla AK, Signal PK. Anti-free radical mechanisms in captopril protection against reperfusion injury in isolated rat hearts. Can J Cardiol 1996; 12: 1099-1104

18 Satoh H, Matsuki K. Electrical and mechanical modulations by oxygen-derived free radical generating systems in guinea pig heart muscles, j Pharm Pharmacol 1997; 49: 505-510

19 De Cavanagh EM, Fraga CG, Ferder L, lnserra F. Enalapril and captopril enhance antioxidant defences in mouse tissues. Am J Physiol 1997; 272: 514-518

20 Kaufmann W, Andreasson K, lsakson P, Worley P. Cyclooxygenases and the central nervous system. Prostaglandins 1997; 54: 601-624

21 ladecola C, Niwa K, Nogawa S, Zhao X, Nagayama M, Araki E, Morham S, Ross ME. Reduced susceptibility to ischemie brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sd USA 2001; 98: 1294-1299

22 Yasojima K, Tourtellotte WW, McGeer EG, McGeer PL. Marked increase in cyclooxygenase-2 in ALS spinal cord. Implications for therapy. Neurology 2001 ; 57: 952-956

23 Aimer G, Guegan C, Teismann P, Naini A, Rosoklija G, Hays AP, Chen C, Przedborski S. Increased expression of the proinflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol 2001 ; 49: 1 76-185

Yasuo Iwasaki*, Yasumitsu Ichikawa*, Osamu lgarashi*, Ken lkeda*[dagger], Shingo Konno*, Joe Aoyagi* and Masao Kinoshita*

* Fourth Department of Internal Medicine, Toho University Ohashi Hospital, Tokyo

[dagger] Department of Neurology, PL Tokyo Health Center, Tokyo, Japan

Correspondence and reprint requests to: Yasuo Iwasaki, MD, The Fourth Department of Internal Medicine, Toho University Ohashi Hospital, 2-17-6 Ohashi Meguro-ku, Tokyo 153-8515, Japan. [] Accepted for publication November 2002.

Copyright Forefront Publishing Group Apr 2003
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