The role of extraocular proprioception in vestibulo-ocular reflex of rabbits.

This study was undertaken to elucidate the role of extraocular proprioception in the vestibulo-ocular reflex, using pigmented rabbits. The presence of extraocular afferent projections in the ophthalmic branch (OB) of the trigeminal nerve was confirmed by retrograde transport of horseradish peroxidase. The OB of the left trigeminal nerve was transected at its junction with the trigeminal ganglion. Vestibular nystagmus was produced by rotating the animal clockwise and counter-clockwise in the horizontal plane in a dark room. The number and direction of the quick phase of nystagmus induced by rotation in the eye on the operated side were not different from those in the eye on the unoperated side or from those before the transection. However, the eye on the operated side moved slowly and unstably without directional preponderance during and after rotation at an angular velocity of 30 degrees/sec. In the sham-operated and unoperated groups, when the angular velocity was increased to over 90 degrees/sec, the eyes deviated in the anticompensatory direction to the head movement (the same direction as the head movement) during and immediately after the rotation. At an angular velocity of over 30 degrees/sec, however, the eye on the operated side exhibited anticompensatory response more frequently and markedly than that on the unoperated side. These results suggest that extraocular proprioception is important for fixation of the eye position in spacial relation to the head, and that loss of the sensation readily induces anticompensatory oculomotor response to head movement.

Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture.

PURPOSE: To examine the effects of methylcobalamin on glutamate-induced neurotoxicity in the cultured retinal neurons. METHODS: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. The neurotoxicity was assessed quantitatively using the trypan blue exclusion method. RESULTS: Glutamate neurotoxicity was prevented by chronic exposure to methylcobalamin and S-adenosylmethionine (SAM), which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and SAM also inhibited the neurotoxicity induced by sodium nitroprusside that release nitric oxide. By contrast, acute exposure to methylcobalamin did not protect retinal neurons against glutamate neurotoxicity. CONCLUSIONS: Chronic administration of methylcobalamin protects cultured retinal neurons against N-methyl-D-aspartate-receptor-mediated glutamate neurotoxicity, probably by altering the membrane properties through SAM-mediated methylation.

Protective action of zinc against glutamate neurotoxicity in cultured retinal neurons.

PURPOSE: To examine the effects of Zn2+ on glutamate-induced neurotoxicity in cultured retinal neurons. METHODS: Primary cultures obtained from fetal rat retinas (16 to 19 days gestation) were used. The neurotoxic effects of excitatory amino acids were quantitatively assessed using the trypan blue exclusion method. RESULTS: A brief exposure of retinal cultures to glutamate or N-methyl-D-aspartate (NMDA) induced delayed cell death. Zn2+ at concentrations of 3 to 30 microM ameliorated glutamate- and NMDA-induced neurotoxicity in a dose-dependent manner. By contrast, neurotoxicity induced by a 1-hour exposure to kainate was not affected by Zn2+. CONCLUSIONS: These findings demonstrate that Zn2+ protects retinal neurons from NMDA receptor-mediated glutamate neurotoxicity.

Protective effects of FK506 against glutamate-induced neurotoxicity in retinal cell culture.

PURPOSE: To examine the effects of FK506 on glutamate neurotoxicity in cultured retinal neurons. METHODS: Experiments were performed with primary retinal cultures obtained from 17- to 19-day-old rat fetuses. To assess the effects of FK506 and other drugs on glutamate neurotoxicity, cultures were treated with a drug beginning 10 minutes before application of glutamate and continuing during the subsequent 10 minutes of glutamate exposure. The treated cells were then incubated for 1 hour in a drug-free and glutamate-free medium. After a 1-hour incubation, cell viability was quantitatively measured by the trypan blue exclusion method. RESULTS: Brief exposure to glutamate markedly decreased cell viability. FK506 protected against glutamate neurotoxicity in a dose-dependent manner. Rapamycin is a competitive inhibitor of FK506 that binds FK506 binding protein. Simultaneous application of rapamycin and FK506 negated the protective effects of FK506. Cyclosporin A, which binds and inhibits calcineurin, mimicked the protective effects of FK506. Treatment with FK506 did not affect the intracellular maximum Ca2+ concentration induced by glutamate application. Although FK506 exhibited protective action against Ca2+ ionophore-induced neurotoxicity, it had no effect on nitric oxide-induced neurotoxicity. Treatment with FK506 reduced the activity of nitric oxide synthase (NOS). CONCLUSION: FK506 protected against glutamate neurotoxicity by inhibiting NOS activity in cultured retinal neurons.

Protective action of dopamine against glutamate neurotoxicity in the retina.

PURPOSE: The electrophysiologic study using patch-clamp techniques demonstrated that NMDA-induced currents had properties similar to those recorded in the brain. METHODS: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. Immunocytochemical and electrophysiologic studies were done to identify the cultured cells. The neurotoxic effects of glutamate or N-methyl-D-aspartate (NMDA) on the retinal cultures were quantitatively assessed using the trypan blue exclusion method. RESULTS: The immunocytochemical study revealed that the major component of the rat retinal cultures was neurons including amacrine cells. The electrophysiologic study using patch-clamp techniques demonstrated that exposure to NMDA-induced currents with properties characteristic of those recorded in the brain. Brief exposure of these neurons to glutamate or NMDA induced delayed cell death. Glutamate neurotoxicity was prevented by the application of dopamine and forskolin. The protective action of dopamine was antagonized by a D1 receptor antagonist (SCH 23390) but not by D2 receptor antagonists (domperidone and sulpiride). A D1 receptor agonist (SKF 38393) protected glutamate-induced neurotoxicity in a concentration-dependent manner, whereas a D2 receptor agonist (quinpirole) did not affect it. CONCLUSIONS: These findings demonstrate that dopamine protects retinal neuronal cells against NMDA receptor-mediated glutamate neurotoxicity via D1 receptors.

Protective effect of bradykinin against glutamate neurotoxicity in cultured rat retinal neurons.

PURPOSE: To identify the localization and expression of bradykinin (BK)-B2 receptors in rat retina and examine the effects of BK on glutamate-induced neurotoxicity using cultured rat retinal neurons. METHODS: An immunohistochemical study using a specific antibody against BK-B2 receptor was performed with rat retina. Primary cultures were obtained from the retina of fetal rats (gestation day 17-19). Expression of BK-B2 receptor mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA obtained from cultured retinal neurons. Cultured cells were exposed to glutamate (1 mM) for 10 minutes and followed by incubation in glutamate-free medium for 1 hour. The effects of BK were assessed by simultaneous application of BK with glutamate. The neurotoxic effects on retinal cultures were quantitatively assessed by the trypan blue exclusion method. RESULTS: Immunohistochemical study demonstrated that BK-B2 receptors were expressed in the ganglion cell, inner nuclear layers, and outer nuclear layers. Furthermore, BK-B2 receptor mRNA expression was observed in cultured retinal neurons. Cell viability was markedly reduced by 10-minute exposure to 1 mM glutamate followed by a 1-hour incubation in glutamate-free medium. Simultaneous application of BK at concentrations of 0.001 to 1 microM with glutamate demonstrated dose-dependent protection against glutamate neurotoxicity. The protective action of BK (1 microM) was inhibited by simultaneous application of BK-B2 receptor antagonist, Hoe140 (1 microM). Furthermore, 1 microM BK had protective effects on neurotoxicity induced by 1 microM ionomycin, a calcium ionophore, and sodium nitroprusside (SNP, 500 microM), a nitric oxide (NO)-generating agent. However, BK did not inhibit neurotoxicity induced by 3-morpholinosydnonimine (SIN-1, 10 microM), an NO and oxygen radical donor. CONCLUSIONS: These results suggest that BK-B2 receptors were distributed in rat retinas and cultured retinal neurons and that BK had a protective action against glutamate neurotoxicity through BK-B2 receptors in cultured retinal neurons. It is suggested that BK-induced protection against glutamate neurotoxicity took place downstream to NO generation and upstream to oxygen radical generation.

When do optic disc edema and peripheral neuropathy constitute poetry?

A patient with chronic, bilateral optic disc edema developed multiple systemic manifestations of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes). A serum immunoelectrophoresis showed an abnormal serum IgG lambda protein, and urine immunoelectrophoresis revealed a monoclonal lambda protein plus an IgG lambda fragment. Bone survey and MRI scan revealed a sclerotic lesion of the first lumbar vertebra, and lymph node biopsy showed changes consistent with Castleman's disease. Thus, his optic disc edema was the presenting feature of the POEMS syndrome and osteosclerotic myeloma.

Beta-receptor involvement in locus coeruleus-induced inhibition of spinal trigeminal nucleus neurons: microiontophoretic and HRP studies.

Microiontophoretic and HRP studies were performed on cats anesthetized with alpha-chloralose to determine whether or not the locus coeruleus (LC)- and noradrenaline (NA)-induced inhibition of relay neurons in the subnucleus oralis of the spinal trigeminal nucleus (STN) is mediated by beta-adrenergic receptors. The inhibition of orthodromic spike generation upon intracranial trigeminal nerve stimulation by LC conditioning stimulation and microiontophoretically applied NA (100-200 nA) was antagonized during microiontophoretic application of sotalol, a beta-adrenergic antagonist, but not affected by phentolamine, an alpha-adrenergic antagonist. When HRP at doses of 300-500 nA was applied for 5-15 min to the immediate vicinity of the STN relay or interneuron, which was electrophysiologically identified by stimulating the ipsilateral trigeminal nerve and contralateral medial lemniscus, the injection site was localized to an area 0.3 mm in diameter and HRP-reactive cells were found in the ipsilateral LC, dorsal raphe nucleus and periaqueductal gray ventral to the aqueduct. These results strongly suggest that NA released from the nerve terminals of LC cells inhibits transmission in the STN relay neuron via beta-adrenergic receptors.

Dual actions of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity in cultured retinal neurons.

This study was performed to elucidate the role of nitric oxide (NO) in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotoxicity in the retina. The experiments were done with primary retinal cultures obtained from 17- to 19-day-old rat fetuses. The NOS activity measured by monitoring the conversion of [3H]arginine to [3H]citrulline was approximately 5 pmol/min/mg protein. A 10-min exposure of the cultured cells to glutamate (1 mM) or NMDA (1 mM) followed by a 1-h incubation in a normal medium consistently resulted in 60% cell death. The concomitant addition of an inhibitor of NOS, Nomega-nitro-L-arginine (300 microM), with glutamate or NMDA reduced cell death by 70%. A brief exposure of the cells to sodium nitroprusside (SNP, 500 microM) or S-nitrosocysteine (SNOC, 500 microM), NO-generating agents, caused 60% cell death. Depletion of NO by reduced hemoglobin prevented the cell death induced by either glutamate, NMDA, or NO generating agents. Fifty microM SNOC alone had no effect on the cell viability. However, pretreatment with 50 microM SNOC as well as simultaneous application of 50 microM SNOC with NMDA inhibited cell death induced by NMDA. These findings indicate that a low concentration of NO plays a protective role in glutamate neurotoxicity via closing the NMDA receptor gated ion channel. However, elevated concentrations of NO, interacting with oxygen radicals, become toxic and mediate glutamate-induced neurotoxicity in the cultured retinal neurons.

Apoptotic DNA fragmentation and upregulation of Bax induced by transient ischemia of the rat retina.

This study was performed to examine the involvement of apoptosis and the expression of bcl-2 family genes in ischemia-induced retinal injury. Retinal ischemia was induced in adult rats by raising the intraocular pressure to 130 mmHg for 45 min. Selective damage to the inner retina was observed 7 days after ischemia. No terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) positive cells were observed in the normal retina, but there was a significant number of TUNEL positive cells 6-48 h after transient ischemia followed by a decrease at 96 and 168 h. The number of TUNEL positive cells reached a maximum at 24 h after ischemia. DNA laddering was observed on agarose gel electrophoresis with the retinas 24 and 48 h after ischemia but not in the normal retina. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed that bax gene expression did not change immediately after cessation of ischemia, but gradually increased as early as 6 h, reached a peak at 24 h, then decreased to near baseline levels at 168 h. On the other hand, bcl-2 gene expression showed no obvious changes at any time after transient ischemia. Moreover, intense Bax protein immunoreactivity was detected in the retinal sections at 24 h after ischemia although little immunoreactivity was present in the normal sections. These results suggest that apoptosis associated with the expression of Bax is involved in retinal cell loss after ischemic insult.

N(omega)-nitro-L-arginine methyl ester protects retinal neurons against N-methyl-D-aspartate-induced neurotoxicity in vivo.

We investigated whether the inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase, affects N-methyl-D-aspartate (NMDA)-induced neurotoxicity in the rat retina in vivo. A single intravitreal injection of NMDA damaged the ganglion cell layer and the inner plexiform layer without affecting the other retinal layers 7 days after injection. Intravitreal injection of (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5, 10-imine hydrogen maleate (MK-801) with NMDA significantly reduced NMDA-induced degeneration of the retina. NMDA-induced degeneration was also prevented by intravitreal injection of L-NAME but not of D-NAME. The protective effect of L-NAME was antagonized by L-arginine. These results suggest that NO plays an important role in NMDA-induced excitotoxic degeneration in the retina.

Effects of B vitamins on glutamate-induced neurotoxicity in retinal cultures.

The effects of B vitamins on glutamate-induced neurotoxicity were examined using primary cultures obtained from the rat retina. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free media for 1 h. Glutamate cytotoxicity was reduced in the cultures that had been maintained in thiamine-, pyridoxine- or nicotinamide-containing medium before the exposure to glutamate. Glutamate cytotoxicity was also reduced by chronic application of thiamine pyrophosphate and pyridoxal phosphate, which are active coenzyme forms of thiamine and pyridoxine, respectively. By contrast, chronic application of riboflavin, pantothenate, biotin, folic acid and inositol did not affect glutamate cytotoxicity. None of the B vitamins tested had any effect on glutamate cytotoxicity when added only during the exposure to glutamate. These findings suggest that chronically applied thiamine, pyridoxine and nicotinamide protect retinal neurons against glutamate cytotoxicity.

Inhibition of NMDA receptors and nitric oxide synthase reduces ischemic injury of the retina.

This study was performed to examine the roles of body temperature, NMDA receptors and nitric oxide (NO) synthase in post-ischemic retinal injury in rats. Cell loss in the ganglion cell layer and thinning of the inner plexiform layer were observed 7 days after ischemia. Cell loss in the ganglion cell layer but not thinning of the inner plexiform layer was reduced by hypothermia during ischemia. Intravenous injection of dizocilpine (MK-801) or Nomega-nitro-L-arginine methyl ester (L-NAME) prior to ischemia ameliorated retinal injury. These results suggest that activation of NO synthase following NMDA receptor stimulation is involved in ischemia-induced retinal injury.

Neuro-Behçet disease presenting with internuclear ophthalmoplegia.

PURPOSE: To report a case of isolated internuclear ophthalmoplegia in a patient with neuro-Behçet's disease. METHOD: We evaluated the patient's clinical course. RESULTS: The patient had isolated internuclear ophthalmoplegia and headache. Subsequent cerebrospinal fluid study revealed marked pleocytosis predominated by lymphocytes (61%) and polymorphonuclear cells (35%), increased protein content, and normal glucose level. A magnetic resonance imaging study with T2-weighted image demonstrated a hyperintense area in the medial longitudinal fasciculus. CONCLUSION: Colchicine treatment of neuro-Behçet's disease caused marked improvement in the symptoms in this case, and the midbrain lesion completely disappeared after treatment.

Progressive visual field defects in patients with intracranial arteriovenous malformations.

Two men, aged 59 and 36 years, had large, intracranial arteriovenous malformations. Both patients developed severe, bilateral visual loss secondary to unrecognized chronic papilledema. Lumbar puncture disclosed increased intracranial pressure. Neuroimaging disclosed only vascular malformations. The patients were treated by embolization of the vascular malformations and ventriculoperitoneal shunting procedures. The malformation of one patient was excised.

Inhibition of vestibular nerve activity by efferent fibres in the cat.

Electrophysiological studies were performed in anesthetized cats to examine the role of the parvocellular reticular nucleus (PCRN) in vestibular afferent fibers originating in the horizontal semicircular canal. When the primary afferent fibres intra-axonally recorded in the brainstem were classified into regular, intermediate, and irregular types, repetitive stimuli over 100 Hz applied to the PCRN inhibited spontaneous firing and the increase in firing during horizontal rotation in irregular and intermediate type units, whereas in regular type units PCRN stimulation affected neither the spontaneous firing nor rotation-induced responses. These results strongly suggest that the PCRN stimulation inhibits the primary afferent terminals of irregular type units receiving impulses from type I hair cells of the ampullae.

[A case with hereditary motor and sensory neuropathy with multiple cranial nerves involvement].

We described a 62-year-old man presenting motor and sensory neuropathy with multiple cranial nerve involvement. He was admitted to our hospital for visual loss and gait disturbance. Visual disturbance appeared at age of 32 and have slowly progressed until admission. At age of 55, he noticed walking difficulty, which has progressed. On neurological examinations we found cranial nerve disturbance including the 2nd, 3rd, 4th, 5th, 6th, 7th and 12th nerves. Muscle atrophy and sensory disturbance were observed in four limbs, most strikingly at the distal lower limbs. The electromyographic study indicated chronic denervation in four limbs. The histological examination on sural nerve biopsy specimens showed neuronal type degeneration accompanied with a severe loss of myelinated fibers and proliferation of perineurial cells in this nerve. We diagnosed the present case as HMSN type 6 documented by Dyck. To our knowledge, the present case has been the initial case accompanied with multiple cranial nerve involvements.

[The role of nitric oxide in the ischemic retina].

Retinal ischemia induces a large increase in the release of glutamate, which exerts its toxic action by way of NMDA (N-methyl-D-aspartate) receptors onto amacrine cells and retinal ganglion cells. Glutamate released during ischemia and especially during reperfusion first stimulates non-NMDA receptors and depolarizes the retinal neurons. As the membrane potentials are depolarized more from the resting membrane potentials, the blockade of NMDA receptors induced by Mg2+ was released. Ca(2+)-influx through the NMDA receptors activates nitric oxide synthase of some amacrine cells, which produce nitric oxide (NO). NO at low concentrations inhibits the NMDA receptors and thereby prevents from retinal neuronal death. By contrast, NO at higher concentrations, interacting with oxygen radicals, becomes toxic and mediates glutamate-induced delayed retinal neuronal death.

[Two cases of systemic lupus erythematosus presenting with disc edema].

We report two young women, 22 and 19 years old, who showed bilateral optic disc edema in the course of systemic lupus erythematosus. Lumbar puncture showed increased intracranial hypertension with no abnormal findings in the composition of the cerebrospinal fluid. Computed tomography and magnetic resonance imaging showed no abnormal findings. They were diagnosed as having rare intracranial hypertension associated with systemic lupus erythematosus. Treatment with systemic corticosteroids produced a dramatic resolution of the increased intracranial hypertension and the disc edema.