Changes in the concentrations of vitamin E analogs and their metabolites in rat liver and kidney after oral administration.

Vitamin E analog, such as α- and γ-tocopherol, can undergo ω-oxidation without cleavage of the chroman ring, and this pathway is responsible for generation of the major urinary vitamin E metabolite, carboxyethyl hydroxychroman. However, it is still unclear how carboxyethyl hydroxychroman is changed in various tissues after vitamin E intake. We therefore investigated changes in the concentrations of α- and γ-tocopherol and their metabolites in rat liver and kidney. The concentration of α-tocopherol in rat liver increased until 6 h after oral administration, and then decreased. The change in the concentration of α-carboxyethyl hydroxychroman in rat liver in the α-Toc group slowly increased until 12 h after oral administration. Cytochrome P450 3A1 mRNA expression significantly increased from 12 h after the start of α-tocopherol administration. The change in the concentration of γ-carboxyethyl hydroxychroman in rat liver in the γ-Toc group markedly increased until 12 h after oral administration. On the other hand, γ-carboxyethyl hydroxychroman in rat kidney showed greater accumulation than α-carboxyethyl hydroxychroman from 3 h to 24 h after oral administration. From these results, we considered that γ-carboxyethyl hydroxychroman formed in the liver continues to be released into the bloodstream and is transported to the kidney rapidly.

Gamma-tocotrienol reduces the triacylglycerol level in rat primary hepatocytes through regulation of fatty acid metabolism.

The present study was carried out to investigate the effect of vitamin E analogs, especially gamma-tocotrienol (γ-T3), on hepatic TG accumulation and enzymes related to fatty acid metabolism in three types of rat primary hepatocytes: (1) normal hepatocytes, (2) hepatocytes incubated in the presence of palmitic acid (PA), and (3) hepatocytes with fat accumulation. Our results showed that γ-T3 significantly reduced the TG content of normal hepatocytes. γ-T3 also increased the expression of carnitine palmitoyltransferase 1 (CPT1A) mRNA, and tended to reduce that of sterol regulatory element binding protein 1c (SREBP-1c) mRNA. In addition, γ-T3 markedly suppressed the gene expression of both C/EBP homologous protein (CHOP) and SREBP-1c induced by PA. As these two genes are located downstream of endoplasmic reticulum (ER) stress, their suppression by γ-T3 might result from a decrease of ER stress. Moreover, γ-T3 suppressed the expression of interleukin 1ß (IL-1ß), which lies downstream of CHOP signaling. Taken together, our data suggest that γ-T3 might prevent hepatic steatosis and ameliorate ER stress and subsequent inflammation in the liver.

Effects of tocotrienol on tumor necrosis factor-α/d-galactosamine-induced steatohepatitis in rats.

It has been reported that α-tocopherol (α-Toc), a vitamin E analog, is effective for treatment of non-alcoholic steatohepatitis (NASH). However, it is unknown whether or not other vitamin E analogs are effective. Therefore we designed a new rat model of steatohepatitis induced by tumor necrosis factor-α (TNF-α) stimulation, and used it to investigate the effects of vitamin E analogs. The rat liver triglyceride content increased with the dosage of TNF-α/d-galactosamine (GalN), but was suppressed by intake of both tocotrienol (T3) and α-tocopherol. Moreover, lipid peroxides (thiobarbituric acid-reactive substances) level in the liver level was also lower in both groups after tocotrienol and α-Toc intake. Intake of both tocotrienol and α-tocopherol also tended to control the increase of liver damage marker activity. In the tocotrienol and α-tocopherol groups, increases of inflammatory cytokines mRNA expression in the liver were inhibited, and these effects were considered to contribute to improvement of inflammation and fibrosis. The expression of mRNAs for inflammatory cytokines in rat primary hepatocytes was increased by TNF-α stimulation, but was inhibited by addition of α-tocotrienol and γ-tocotrienol. Transforming growth factor-ß1 mRNA expression in particular was significantly inhibited by γ-tocotrienol. These findings suggest that tocotrienol species are effective for amelioration of steatohepatitis, and that tocotrienol and α-tocopherol exert a synergistic effect.

High affinity of interaction between superantigen and T cell receptor Vbeta molecules induces a high level and prolonged expansion of superantigen-reactive CD4+ T cells.

In mice implanted with an osmotic pump filled with the superantigen (SAG) staphylococcal enterotoxin A (SEA), the Vß3(+)CD4(+) T cells exhibited a high level of expansion whereas the Vß11(+)CD4(+) T cells exhibited a mild level of expansion. In contrast, in mice implanted with an osmotic pump filled with SE-like type P (SElP, 78.1% homologous with SEA), the Vß11(+)CD4(+) T cells exhibited a high level of expansion while the Vß3(+)CD4(+) T cells exhibited a low level of expansion, suggesting that the level of the SAG-induced response is determined by the affinities between the TCR Vß molecules and SAG. Analyses using several hybrids of SEA and SElP showed that residue 206 of SEA determines the response levels of Vß3(+)CD4(+) and Vß11(+)CD4(+) T cells both in vitro and in vivo. Analyses using the above-mentioned hybrids showed that the binding affinities between SEA and the Vß3/Vß11 ß chains and between SEA-MHC class II-molecule complex and Vß3(+)/Vß11(+) CD4(+) T cells determines the response levels of the SAG-reactive T cells both in vitro and in vivo.

Morphological and biochemical analysis of intact and opaque cornea in dogs.

The arrangement of collagen fibrils and glycosaminoglycans (GAGs) in substantia propria are important for maintaining transparency of the cornea. Interferences in collagen fibrils and GAG production could be adversative to corneal integrity. In this study, six dogs consisting of four Beagles with normal cornea (normal), one Beagles with opaque cornea (sample No. 1) and one Shih Tzu with neovascularization opaque cornea (sample No.2) were used. All samples were observed morphologically by light and electron microscopes to obtain diameter and distribution of collagen fibrils in substantia propria and were performed biochemically to investigate into GAGs and collagen types. The average diameter of collagen fibrils in the intact cornea of normal, sample No.1 and No.2 was 33.2, 35.0 and 25.0 nm, respectively. The percentage of matrix per unit area was 67% in normal, 87% in sample No.1 and 28.3% in sample No.2. The type III collagen ratio was 25.3% in normal, 21.3% in sample No.1 and 35.8% in sample No.2. The relative amount of heparan sulfate, chondroitin sulfate, dermatan sulfate and keratin sulfate was 1.5, 9.7, 51.1 and 37.7% in normal, 3.3, 26.0, 45.7 and 23.7% in sample No.1 and 1.2, 18.0, 16.6 and 54.1% in sample No.2. Hyaluronic acid was found only in sample No.1 with a relative amount of 1.3%. Since there was some relationship between collagen formation and GAGs composition, it might be speculated that disturbance in arrangement of collagen fibrils and GAG metabolism especially in substantia propria would bring up opacity of the cornea.

Expression of newly identified secretory CEACAM1(a) isoforms in the intestinal epithelium.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates intestinal immunological homeostasis. However, precise expression patterns of CEACAM1 isoforms remain poorly understood in the intestinal epithelia. Focusing on the small intestinal epithelium of BALB/c mice, we identified three novel splice variants encoding CEACAM1(a)-2, -2C1, and -4C1 by RT-PCR. CEACAM1(a)-2, -2C1, and -4C1 demonstrated secretory properties by transfection experiments in vitro. Among them, CEACAM1(a)-4C1 was the major secreted isoform in vivo due to the soluble/secreted CEACAM1(a) with a frameshift sequence in the C-terminus, specific for CEACAM1(a)-2C1 and -4C1. CEACAM1(a)-4C1 was capable of binding murine hepatitis virus (MHV) and was detected at approximately 120kDa in the small intestinal secretions. Neutralizing effects of the soluble CEACAM1(a) on MHV infectivity in vitro were demonstrated by using recombinant CEACAM1(a)-4C1. Our data suggest an intrinsic mechanism operated by free CEACAM1 for surveillance of pathogens and maintenance of homeostasis in the intestine.

Tocotrienol suppresses adipocyte differentiation and Akt phosphorylation in 3T3-L1 preadipocytes.

In vivo studies show that alpha-tocotrienol and gamma-tocotrienol accumulate in adipose tissue. Furthermore, a recent study reports that the oral administration of gamma-tocotrienol from a tocotrienol-rich fraction from palm oil (TRF) decreases body fat levels in rats. The objective of this study was to evaluate the effect of TRF and its components on adipocyte differentiation in 3T3-L1 preadipocytes, which differentiated into adipocytes in the presence of 1.8 micromol/L insulin. TRF suppressed the insulin-induced mRNA expression of adipocyte-specific genes such as PPARgamma, adipocyte fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha) compared with the differentiation of 3T3-L1 preadipocytes into adipocytes only in the presence of insulin. To confirm the suppressive effect of TRF, the major components of TRF, such as alpha-tocotrienol, gamma-tocotrienol, and alpha-tocopherol, were investigated. Alpha-tocotrienol and gamma-tocotrienol decreased the insulin-induced PPARgamma mRNA expression by 55 and 90%, respectively, compared with insulin, whereas alpha-tocopherol increased the mRNA expression. In addition, gamma-tocotrienol suppressed the insulin-induced aP2 and C/EBPalpha mRNA expression, triglyceride accumulation, and PPARgamma protein levels compared with insulin. The current results also revealed that gamma-tocotrienol inhibited the insulin-stimulated phosphorylation of Akt but not extracellular signal-regulated kinase (ERK)1/2 in the insulin signaling pathway of 3T3-L1 preadipocytes. Thus, the antiadipogenic effect of TRF depends on alpha-tocotrienol and gamma-tocotrienol, and gamma-tocotrienol may be a more potent inhibitor of adipogenesis than alpha-tocotrienol. Therefore, the results of this study suggest that tocotrienol suppresses insulin-induced differentiation and Akt phosphorylation in 3T3-L1 preadipocytes. Furthermore, tocotrienol could act as an antiadipogenic vitamin in the nutrient-mediated regulation of body fat through its effects on differentiation.

Reduction in the motor unit number estimate (MUNE) after cerebral infarction.

We examined the relationship between the degree to which motor unit number estimates (MUNEs) decrease in association with the clinical features of patients with the infarction. Using a multiple-point stimulation technique, we obtained the MUNE of the hypothenar muscle group in 13 age-matched control subjects and 30 patients with cerebral infarction. In all patients, we obtained the Japan Stroke Scale (JSS) and head MR images. In 8 patients with acute cerebral infarction, admitted within 24 h after onset, we also obtained head MR angiograms and single-photon emission CT. There was a decrease in the MUNE of the hypothenar muscle group on the affected side of 24 patients with cerebral infarction and hand weakness. The decrease in the MUNE started from 4 to 30 h after the infarction, when T1-weighted MR images of the brain involved were normal. The degree to which the MUNE decreased correlated with the part of the JSS showing the upper extremity weakness. A decrease in the MUNE of the hypothenar muscle group within 30 h after cerebral infarction may be due to transsynaptic inhibition of the spinal alpha motor neurons innervating this muscle.

Peyer's patches are required for intestinal immunoglobulin A responses to Salmonella spp.

Previous studies have shown that Peyer's patches (PP) are not required for intestinal immunoglobulin A (IgA) responses to orally administered soluble protein. However, the roles of PP in regulation of mucosal immune responses against bacterial antigen remain to be clarified. In the present study, we generated several gut-associated lymphoreticular tissue-null mice by treatment with anti-interleukin-7 receptor antibody, the fusion protein of lymphotoxin beta receptor and IgG Fc, and/or tumor necrosis factor receptor p55 and IgG Fc. These mice were then immunized with recombinant Salmonella expressing the C fragment of the tetanus toxin (rSalmonella-Tox C). Orally immunized PP-null mice as well as isolated lymphoid follicle (ILF)-null, PP/ILF-null, and PP/ILF/mesenteric lymph node-null mice induced identical levels of tetanus toxoid (TT)-specific systemic IgG responses to those of control mice. However, PP-null mice, but not ILF-null mice, failed to induce TT-specific intestinal IgA antibodies. Analysis of TT-specific CD4+ T-cell responses showed a reduction of gamma interferon (IFN-gamma) synthesis in the intestinal lamina propriae of PP-null mice given oral rSalmonella-Tox C. In contrast, TT-specific IFN-gamma responses in the spleen and delayed-type hypersensitivity responses were intact in those immunized mice. Interestingly, Salmonella lipopolysaccharide (LPS)-specific fecal IgA responses were not elicited in PP-null mice, while serum IgG anti-LPS antibodies were identical to those of control mice. These results suggest that while none of the gut-associated lymphoreticular tissues are required for the induction of systemic immune responses, PP are an essential lymphoid tissue for induction and regulation of intestinal IgA immunity against orally administered rSalmonella.

A case of Vernet syndrome with varicella zoster virus infection.

A 40-year-old man was admitted to our department, because of sudden onset of dysphagia, hoarseness, left neck pain and headache. There were no skin lesions. On neurological examination, there were paralysis of the left soft palate and constrictor muscles of the pharynx, weakness of the left sternocleidomastoid and left upper trapezius. In cerebrospinal fluid (CSF) examination, cell count and protein concentration were elevated. Antibody titer to varicella zoster virus (VZV) was elevated in both the serum and CSF. And VZV-DNA was detected by PCR from CSF. Gd enhanced MRI showed the nodular lesion at the left jugular foramen. The diagnosis of Vernet's syndrome (VS) associated with VZV infection was made. The patient's symptoms were immediately improved with 30 mg of prednisone and 3 g of varaciclovir daily for 14 days. Only a few cases of VS due to VZV have been reported previously. Our case is the first case that detected VZV-DNA in CSF by PCR.

The coantioxidative effects of carboxyethyl-6-hydroxychromans and alpha-Tocopherol.

alpha-Tocopherol (alpha-Toc) is abundant in LDL and thought to prevent the oxidation of LDL together with various water-soluble antioxidants. Recently, it was reported that alpha-Toc and gamma-Toc metabolites, alpha-carboxyethyl-6-hydroxychromans (CEHC) and gamma-CEHC, are water-soluble antioxidants. In this study, we investigated the interaction between alpha-Toc and CEHC against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals and LDL oxidation. We administered 600 mg of alpha-Toc to healthy male volunteers to obtain LDL including high levels of alpha-Toc before antioxidant administration. The alpha-Toc content of their LDL was increased after consumption at 24 h (18.3 microg/mL) above the level before consumption (6.6 microg/mL). The lag time of LDL at 24 h after alpha-Toc consumption (alpha-Toc rich LDL) with alpha-CEHC (98.5+/-8.2 min) or gamma-CEHC (101.3+/-9.0 min) was longer than that of only alpha-Toc-rich LDL (78.1+/-9.0 min). Furthermore, we examined the interaction of LDL with CEHC and alpha-Toc in vitro (5-20 microg/mL). The lag times of 5 and 10 microg/mL alpha-Toc were 65.5+/-18.9 min and 69.5+/-15.5 min, and that of 20 microg/mL alpha-Toc (83.5+/-20.2 min) was longer than the control value (55.7+/-14.1 min). The lag time of 20 microg/mL alpha-Toc with alpha-CEHC (98.7+/-25.7 min) or gamma-CEHC (100.6+/-25.3 min) was longer than that of only alpha-Toc (83.5+/-20.2 min). These results suggest that CEHC has the potential to delay the oxidation of LDL, while enhancing the antioxidative activity of alpha-Toc both in vitro and ex vivo.

Indocyanine green angiography for examining the normal ocular fundus in dogs.

In dogs, a variety of diseases of the retina and choroid have been reported, either separately or concomitantly; however, the canine choroid is difficult to evaluate by veterinary techniques currently available. Indocyanine green (ICG) angiography is widely used in human ophthalmology, but has not been investigated for use in canine ophthalmology. The aim of this study was to apply a new approach to ICG angiography and compare the resulting angiograms with fluorescein (FLUO) angiograms of the ocular fundus in dogs. With a fundus camera equipped with an infrared-sensitive charged coupled device (CCD), we performed angiography on eight healthy beagles under inhalation anesthesia. ICG angiography enabled clear visualization of the choroidal vasculature, whereas FLUO angiography showed only the retinal vessels. At 8.4 +/- 3.6 sec after administration of ICG dye into the cephalic vein, the choroidal arteries could be seen extending radially from the optic disc, then the choroidal veins became apparent at 10.2 +/- 4.1 sec, coursing alongside the choroidal arteries. Gradual fading of the choroidal vessels began 13.2 +/- 2.2 min after the dye was administered, and overall diffuse fluorescence of the fundus appeared. Diffuse fluorescence of the fundus continued after the choroidal vessels and optic disc faded at about 58.3 +/- 5.3 min from administration of the dye. In conclusion, ICG angiography provides clear resolution and is reliable and simple, thus offering promise as a diagnostic aid for clinical evaluation of the choroid in dogs.

gamma-Tocopherol Accelerated Sodium Excretion in a Dose-Dependent Manner in Rats with a High Sodium Intake.

We have previously reported that gamma-tocopherol (gamma-Toc) displays a natriuretic potency in rats fed a NaCl diet and administered 20 mg gamma-Toc. In this study, we investigated whether gamma-Toc has natriuretic potency at a dose lower or higher than 20 mg in rats given a NaCl diet. Male rats were fed a control diet or a NaCl diet and administered either placebo or 10, 20 or 40 mg of gamma-Toc. The rat urine was collected for 24 hours (divided into 6 hour periods) and the 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) level, the sodium excretion content, and the urine volume were determined. The 24-hour gamma-CEHC and sodium levels in the urine of the NaCl groups given 20 mg or 40 mg gamma-Toc were significantly higher than those in the placebo group. The peak levels of urine sodium and gamma-CEHC in the NaCl group given 40 mg gamma-Toc appeared at 0-6 h, which was a more rapid increase than that seen in the group given 20 mg gamma-Toc. The 24-hour urine volumes of the NaCl groups given 10 and 20 mg gamma-Toc were significantly higher than the urine volume of the placebo group. Our findings suggested that gamma-Toc increased sodium excretion in a dose-dependent manner in rats fed a NaCl diet. Moreover, a high dose of gamma-Toc may accelerate its metabolism and cause an increase in the rate of sodium excretion.

Reduction in the motor unit number estimate (MUNE) after cerebral infarction.

BACKGROUND: The mechanism of the decrease in motor unit number estimates (MUNEs) after cerebral infarction has not been studied systematically. We examined the relationship between the degree to which MUNEs decreased and the other clinical features of patients with the infarction. METHODS: Using a multiple point stimulation technique, we obtained the MUNE of the hypothenar muscle group in 13 age-matched control subjects and 30 patients with cerebral infarction. In all patients, we obtained the Japan Stroke Scale (JSS) and head MR images. In eight patients with acute cerebral infarction, admitted within 24 h after onset, we also obtained head MR angiograms and single-photon emission CT. FINDINGS: There was a decrease in the MUNE of the hypothenar muscle group on the affected side of 24 patients with cerebral infarction and hand weakness. The decrease in the MUNE started from 4 to 30 h after the infarction, when T1-weighted MR images of the brain involved were normal. The degree to which the MUNE decreased correlated with the part of the JSS showing the upper extremity weakness. INTERPRETATIONS: A decrease in the MUNE of the hypothenar muscle group within 30 h after cerebral infarction may be due to trans-synaptic inhibition of the spinal alpha motor neurons innervating this muscle.

Cheiro-oral-pedal syndrome due to brainstem hemorrhage.

Cheiro-oral-pedal syndrome is characterized by specific sensory disturbance around the corner of the mouth, in the hand and in the foot on the same side. Lesions responsible for causing this syndrome vary. We report two cases of cheiro-oral-pedal syndrome due to midbrain and pontine hemorrhage, respectively. Pontine hemorrhage producing cheiro-oral-pedal syndrome has been reported in three cases, but this is the first case that midbrain hematoma exhibits this syndrome. Damage in the sensory pathway can cause cheiro-oral-pedal syndrome. Difference in the threshold may explain the specific sensory pattern in this syndrome. Cheiro-oral-pedal syndrome is caused by lacunar infarction in majority of the cases. However, it should be kept in mind that hematomas can cause cheiro-oral-pedal syndrome.

Cheiro-pedal syndrome following pontine infarction.

We report the case of a 64-year-old man with sudden onset of numbness in the right hand and foot. Neurological examinations were normal except for hypersthesia, and hyperalgesia of the right hand and foot. Brain MRI demonstrated a high signal intensity on T2-weighted image and a low signal intensity on T1-weighted image in the left tegmetum of the pons. He was diagnosed with pontine infarction presenting with cheiro-pedal syndrome (CPS). Damage in the sensory pathways can cause CPS. Difference in the threshold may explain the specific sensory pattern in this syndrome. Further examination of the relationship between sensory symptoms and localization on MRI is needed to clarify this syndrome.

Effects of margarine containing medium-chain triacylglycerols on body fat reduction in humans.

We found previously that the ingestion of margarine containing medium-chain triacylglycerols (MCT) resulted in a significant increase in postprandial thermogenesis when compared with long-chain triacylglycerols (LCT). Diets that included margarine containing MCT and LCT were compared for 12 weeks in 73 subjects to investigate the effects on body weight, body fat, areas of subcutaneous and visceral fat, serum total cholesterols, triglycerides, lipoproteins, plasma glucose, serum insulin, total ketone bodies, and the activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase. We conducted a double-blind, controlled study and used blended rapeseed oil and soybean oil (LCT) as a comparison. Two groups ingested 2100-2400 kcal/day of energy, 65-73 g/day of total fat, and 14 g/day of test margarine (5 g/day of MCT or LCT). The subjects on the MCT diet demonstrated significant decreases in body fat weight (- 3.8 +/- 2.4 kg vs - 2.4 +/- 1.7 kg; MCT vs LCT, mean +/- SD), subcutaneous fat (- 38.2 +/- 29.9 cm(2) vs - 22.6 +/- 19.3 cm(2)), and visceral fat (- 12.2 +/- 11.2 cm(2) vs - 1.6 +/- 12.8 cm(2)) after 12 weeks. There were no clinical differences in measured blood parameters. We suggest that the postprandial increase in thermogenesis and control of postprandial triglyceride levels may explain these results.

Trophic effect of olmesartan, a novel AT1R antagonist, on spinal motor neurons in vitro and in vivo.

Olmesartan is a novel compound which has been shown to exhibit various neuropharmacological effects. For the purpose of clarifying the effect of Olmesartan on spinal motor neurons, we studied the following tests. We studied the effect in vitro of Olmesartan on neurite outgrowth and choline acetyltransferase (ChAT) activity in primary explant cultures of ventral spinal cord (VSCC) of fetal rats. Olmesartan-treated VSCC, compared with control VSCC, had a significant neurite outgrowth and increased activity of ChAT. The effect was dose-related in neurite outgrowth. However, there was no relationship between activity of ChAT andgiven doses of Olmesartan. We examined in vivo the effect of Olmesartan on axotomized spinal motor neuron death in the rat spinal cord. After post-natal unilateral section of sciatic nerve, there was approximately a 50% survival of motor neurons in the fourth lumbar segment. In comparison with vehicle, intraperitoneal injection of Olmesartan for consecutive 14 days reduced spinal motor neuron death. There was no relationship between number of surviving neurons and doses of Olmesartan. These in vitro and in vivo studies showed that Olmesartan has a neurotrophic effect on spinal motor neurons. Our data suggest a potential therapeutic use of Olmesartan in treating diseases that involve degeneration and death of motor neurons, such as motor neuropathy and amyotrophic lateral sclerosis.

Temocapril prevents motor neuron damage and upregulation of cyclooxygenase-II in glutamate-induced neurotoxicity.

To examine the possible neuroprotective effect of temocapril, one kind of angiotensin-converting enzyme inhibitor, against glutamate-induced neurotoxicity, we analyzed the pharmacologic utility of temocapril in a post-natal organotypic culture model of motor neuron degeneration. Treatment with 10(-5) M of glutamate resulted in a motor neuron loss and decreased activity of choline acetyltransferase (ChAT). Cotreatment of 10(-5) M of glutamate and temocapril revealed protective effect on motor neuron death and decreased activity of ChAT. Next we performed reverse transcription-PCR analysis for cyclooxygenase-II (COX-II). COD-II mRNA 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.

Neuroprotective actions of FK506 and cyclosporin A on motor neuron survival following neonatal axotomy.

We show that nonimmunosuppressive analogues of the immunosuppressive drugs FK506 and cyclosporin A (CsA) rescue axotomized neonatal motor neuron death. Unilateral sciatic nerve was transected in neonatal rats. Animals were then treated daily with different doses of FK506 and CsA for 14 days with intraperitoneal injection. Control rats received phosphate buffer saline (PBS) in the same fashion. After treatment, the number of spinal motor neurons was determined at L4 level. In comparison with vehicle, both FK506 (5.0 mg kg(-1)) and CsA (10.0 mg kg(-1)) rescued motor neuron death in a similar way. These results indicate therapeutic relevance in the treatment of damaged motor neuron disorders, such as motor neuropathy or amyotrophic lateral sclerosis.