Nozomu Tagaya

Coadministration of interleukin-6 (IL-6) and soluble IL-6 receptor delays progression of wobbler mouse motor neuron disease

Interleukin-6 (IL-6), a multipotential cytokine, initiates signal transduction pathways similar to those of ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF). These molecules share the signal transducing receptor component, gp130. IL-6 triggers homodimerization of gp130, whereas CNTF and LIF induce heterodimerization of gp130 and LIF receptor. Although CNTF or LIF treatment attenuates motor deficits in wobbler mouse motor neuron disease (MND), neuroprotective effects of IL-6 on this animal have not yet been clarified. Here we studied whether simultaneous treatment with IL-6 and soluble IL-6 receptor (sIL-6R) can ameliorate symptomatic and neuropathological changes in wobbler mouse MND. After clinical diagnosis at postnatal age 3-4 weeks, wobbler mice received subcutaneous injection with human recombinant IL-6 (1.0 mg/kg), human sIL-6R (0.5 mg/kg), IL-6 + sIL-6R or vehicle, daily for 4 weeks in a blind fashion. Compared to vehicle, coadministration with IL-6 and sIL-6R potentiated grip strength, attenuated muscle contractures in the forelimbs, reduced denervation muscle atrophy and prevented degeneration of spinal motor neurons. Single administration with IL-6 or sIL-6R did not retard the symptomatic and neuropathological progression, although IL-6-treated mice did not raise anti-IL-6 antibodies. Treatment with IL-6 + sIL-6R, but not with IL-6 or sIL-6R alone delayed progression of wobbler mouse MND. Our results indicate that the neuroprotective mechanism for IL-6/sIL-6R on wobbler mouse MND differs from that of CNTF or LIF alone. We hypothesize that IL-6/sIL-6R complex may function on motor neurons through activation and homodimerization of gp130.

Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons

Deprenyl, a selective monoamine oxidase B inhibitor, is effective in Parkinsons disease, and can slow the cognitive deterioration in Alzheimers disease. However, it is not known whether this agent has a trophic effect on spinal motor neurons. We have studied neurotrophic effects of deprenyl on spinal motor neurons, using explanted ventral spinal cord culture from 13-day-old rat embryos. Deprenyl-treated cultures significantly enhanced neurite outgrowth with cultures of ventral spinal cord. Our data suggest that deprenyl is one of the candidate for neurotrophic factors on spinal motor neurons in vitro. A possible role for deprenyl in amyotrophic lateral sclerosis remains to be defined.

Effect of transforming growth factor β1 on spinal motor neurons after axotomy

Abstract Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor β (TGF-β) family, has potent effects on developing motor neurons. TGF are pluripotent cytokines that exert biological effects on a variety of neurons. TGF β 1 , on the other hand, promotes motor neuron survival in vitro and saves motor neurons from naturally occurring cell death. Here we investigate the neurotrophic effects of TGF β 1 , for axotomized motor neuron death. The sciatic nerve was cut in newborn rats and TGF β 1 , was injected, either by intraperitoneally or by lesion site, for 14 days after transection. Two or six weeks postlesion, the number and the diameter of motor neurons was assessed. TGF β 1 , significantly attenuated axotomy induced motor neuron death by intraperitoneal administration or by lesion site administration at 2 weeks after neonatal axotomy in a similar way. However, no effect was observed at 6 weeks after nerve lesion, despite continuous application of TGF β 1 , daily for 14 days. These results indicate that TGF β 1 , can prevent the death of motor neurons in vivo, but it cannot permanently rescue lesioned motor neurons.

Lecithinized superoxide dismutase retards wobbler mouse motoneuron disease

Gene mutations of Cu/Zn superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Oxidative stress also plays a role in the pathogenesis of sporadic ALS. Whether antioxidant therapy is beneficial in this fatal disease is now crucial. We have shown that SOD treatment improves neuromuscular dysfunction and morphological changes in wobbler mouse motoneuron disease. Progressive spinal motor neuronopathy and axonopathy, predominantly in the cervical cord, occur at postnatal age 3-4 weeks, leading to muscle weakness and contracture of the forelimbs in this animal. These motor deficits rapidly increase by postnatal age 6-8 weeks, and then slowly progress. Wobbler mice were given two doses daily of phosphatidyl choline-bound Cu/Zn SOD (PC-SOD, 10(4), 10(5) U/kg) or a vehicle solution by intraperitoneal injection from postnatal 3-4 to postnatal 7-8 weeks of age. PC-SOD treatment attenuated progression of motor dysfunction, prevented denervation muscle atrophy, and delayed degeneration of spinal motoneurons in wobbler mice. This raises the possibility that PC-SOD may have therapeutic potential in human motoneuron disease.

Deprenyl and pergolide rescue spinal motor neurons from axotomy-induced neuronal death in the neonatal rat

It has been reported that both the monoamine oxidase inhibitor, deprenyl and the dopamine receptor agonist, pergolide have neuroprotective actions. To investigate the effect of deprenyl and pergolide on axotomized motor neuron death, we examined the survival of spinal motor neurons after sciatic nerve transection in the neonatal rats. Newborn rats were anesthetized with hypothermia. Sciatic nerve was cut near the obturator tendon in the left thigh. Animals were then treated daily with deprenyl (10 mg kg(-1)), pergolide (5 mg kg(-1)), or PBS for 14 days with intraperitoneal injections in a blind fashion. After the treatment, the number of spinal motor neurons in the L 4-6 was counted. There was approximately a 50% loss of spinal motor neurons in PBS-treated group. By contrast, both deprenyl and pergolide prevents spinal motor neuron death after axotomy Co-administration of deprenyl and pergolide is more effective than either agent alone but not significant. These findings are consistent with the idea that deprenyl and pergolide are survival factors for developing spinal motor neurons.

Neuroprotective effect of basic fibroblast growth factor on wobbler mouse motor neuron disease.

Basic fibroblast growth factor (bFGF) possesses neuroprotective effects on a variety of neurons. Here we report that it delays progression of motor neuron disease (MND) in the wobbler mouse. After initial diagnosis of MND at post-natal age 3-4 weeks, wobbler mice receive either recombinant human bFGF (1 mg kg-1, n = 10) or vehicle (n = 10), daily for weeks by subcutaneous injection in a blind fashion. We performed symptomatic and neuropathological assessments in both groups. The treatment was fulfilled at 7-8 weeks of age. In comparison with vehicle, bFGF treatment potentiated grip strength (p < 0.008), attenuated forelimb contracture (p < 0.003), and increased weight of the biceps muscle (p < 0.008). bFGF-treated mice retarded denervation muscle atrophy (p < 0.001) and degeneration of spinal motoneurons (p < 0.001). Our study shows that bFGF treatment is beneficial in a murine MND model. We provide a rationale that bFGF may have therapeutic potential in peripheral motor neuropathy or MND.

Magnetic resonance imaging and neuropathological findings in two patients with Creutzfeldt-Jakob disease

We report 2 autopsy-proven patients with Creutzfeldt-Jakob disease (CJD) showing bilateral decreased signal intensity in the thalamus on T2-weighted images. On post-mortem examination, all affected areas showed the characteristic features of CJD, such as neuronal loss, gliosis, and status spongiosus. These findings are another distinctive MRI appearance in CJD.

Basic fibroblast growth factor and platelet-derived growth factor prevent the death of spinal. motor neurons after sciatic nerve transection in the neonatal rats

In vivo, motor neurons are destined to die after axotomy. Several neuronal growth factors, such as ciliary neurotrophic factor, brain-derived neurotrophic factor, and leukemia inhibitory factor rescue neuronal death of axotomized motor neurons. Here, we report that systemically administered basic fibroblast growth factor and platelet-derived growth factor prevented spinal motor neuron death in neonatal rats following sciatic nerve resection. These data indicate that basic fibroblast growth factor and platelet derived growth factor play a role for motor neuron survival in vivo.

Acidic and basic fibroblast growth factors enhance neurite outgrowth in cultured rat spinal cord neurons

We have studied neurotrophic effects of acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) on explanted ventral and dorsal spinal cord cultures from 13- and 14-day-old rat embryos. Cultures treated with aFGF and bFGF significantly enhanced neurite outgrowth with cultures of ventral spinal cord, but not with cultures of dorsal spinal cord. Our data suggest that aFGF and bFGF are potent neurotrophic factors on rat ventral spinal cord neurons in vitro.

TRH-analog, TA-0910 (3-methyl-(s)-5,6-dihydroorotyl-L-histidyl-L-prolinamide) rescues motor neurons from axotomy-induced cell death.

TA-0910 (3-methyl-(s)-5,6-dihydroorotyl-L-histidyl-L-prolinamide) is a potent and long acting TRH analog. We have studied the effect of TA-0910 on axotomy-induced neuronal death. The left sciatic nerve was transected in neonatal rats. TA-0910 or vehicle was administered on consecutive 14 days with intraperitoneal injections. After the treatment, the number of spinal motor neurons and the motor neuron diameter was assessed at the level of L4-6 segments. In comparison with vehicle, TA-0910 significantly prevented the death of motor neurons and preserved the motor neuron diameter on the lesioned side. These results suggest that TA-0910 is a survival factor for developing spinal motor neurons.