Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that selectively affects the motor neurons. The details of the mechanisms of selective motor-neuron death remain unknown and no effective therapy has been developed. We investigated the therapy with bone-marrow mononuclear cells (BMMC) in a mouse model of ALS (SOD1(G93A) mice). METHODS: We injected 10(6) BMMC into the lumbar portion of the spinal cord of SOD1(G93A) mice in presymptomatic (9 weeks old) and symptomatic (14 weeks old) phases. In each condition, we analyzed the progression of disease and the lifespan of the animals. RESULTS: We observed a mild transitory delay in the disease progression in the animals injected with BMMC in the presymptomatic phase. However, we observed no increase in the lifespan. When we injected BMMC in the symptomatic phase, we observed no difference in the animals' lifespan or in the disease progression. Immunohistochemistry for NeuN showed a decrease in the number of motor neurons during the course of the disease, and this decrease was not affected by either treatment. Using different strategies to track the BMMC, we noted that few cells remained in the spinal cord after transplantation. This observation could explain why the BMMC therapy had only a transitory effect. CONCLUSION: This is the first report of intraspinal BMMC therapy in a mouse model of ALS. We conclude this cellular therapy has only a mild transitory effect when performed in the presymptomatic phase of the disease.

Spinal inhibitory circuits and their role in motor neuron degeneration.

In the spinal cord neuronal activity is controlled by the balance between excitatory and inhibitory neurotransmission, mediated mainly by the neurotransmitters glutamate and GABA/glycine, respectively. Alterations of this equilibrium have been associated with spinal motor neuron hyperexcitability and degeneration, which can be induced by excitotoxicity or by decreasing inhibitory neurotransmission. Here we review the ventral horn neuronal network and the possible involvement of inhibitory circuits in the mechanisms of degeneration of motor neurons characteristic of amyotrophic lateral sclerosis (ALS). Whereas glutamate mediated excitotoxicity seems to be an important factor, recent experimental and histopathological evidence argue in favor of a decreased activity of the inhibitory circuits controlling motor neuron excitability, mainly the recurrent inhibition exerted by Renshaw cells. A decreased Renshaw cell activity may be caused by cell loss or by a reduction of its inhibitory action secondary to a decreased excitation from cholinergic interneurons. Ultimately, inhibitory failure by either mechanism might lead to motor neuron degeneration, and this suggests inhibitory circuits and Renshaw cells as pharmacologic targets for ALS treatment.

Normative data of F-wave measures in China.

OBJECTIVE: To establish normal ranges of F-wave measures in China as compared to published data in Brazil and Japan. METHOD: We studied F waves in 127 healthy Chinese subjects, aged 21-78 years old, stimulating the median, ulnar, tibial and peroneal nerves distally and proximaly. RESULT: The F-wave latencies had a linear correlation to the subject height in all nerves tested, showing a steeper (P < 0.05) regression line in Brazil compared to China and Japan for the tibial nerve. The Chinese population also had a higher distally elicited F-wave persistence and faster F wave conduction velocities than previously reported for both ulnar and tibial nerves. These values showed significant difference (P < 0.05) compared to Brazil but not to Japan. CONCLUSION: F-wave latencies show a linear correlation to subject height, although the slope of regression lines varies among countries, reflecting the difference in F-wave persistence and F-wave conduction velocity. SIGNIFICANCE: Our study provides a rational for the use of a latency-height nomogram in clinical studies and underscores the importance of developing country specific normative data.

Tonic inhibition in spinal ventral horn interneurons mediated by α5 subunit-containing GABA(A) receptors.

GABA(A) receptors mediate synaptic and tonic inhibition in many neurons of the central nervous system. These receptors can be constructed from a range of different subunits deriving from seven identified families. Among these subunits, α(5) has been shown to mediate GABAergic tonic inhibitory currents in neurons from supraspinal nuclei. Likewise, immunohistochemical and in situ hybridization studies have shown the presence of the α(5) subunit in spinal cord neurons, though almost nothing is known about its function. In the present report, using slices of the adult turtle spinal cord as a model system we have recorded a tonic inhibitory current in ventral horn interneurons (VHIs) and determined the functional contribution of the α(5) subunit-containing GABA(A) receptors to this current. Patch clamp studies show that the GABAergic tonic inhibitory current in VHIs is not affected by the application of antagonists of the α(4/6) subunit-containing GABA(A) receptors, but is sensitive to L-655708, an antagonist of the GABA(A) receptors containing α(5) subunits. Last, by using RT-PCR and immunohistochemistry we confirmed the expression of the α(5) subunit in the turtle spinal cord. Together, these results suggest that GABA(A) receptors containing the α(5) subunit mediate the tonic inhibitory currents observed in VHIs.

Spontaneous electromyographic potentials in chronic spinal cord injured patients: relation to spasticity and length of nerve.

Nine patients with complete cervical spinal cord injury (SCI) had their vastus medialis, tibialis anterior, and gastrocnemius muscles evaluated with an electromyographic (EMG) examination in the acute (four to eight weeks) and chronic (more than one year) phases. The hypothesis that spontaneous EMG activity changes with time was assessed. During the chronic phase evaluation, a conduction study was performed to rule out peripheral nerve damage, and the amount of reflex activity was assessed on a scale of 0 to 5 (0 = areflexia; 5 = greater than 5 beats of clonus) to estimate the amount of spasticity. Subjects demonstrated normal conduction through the sensory (sural nerve) and/or motor segments of the peroneal and tibial nerves. In the acute phase, each muscle had spontaneous activity with no significant variation between different muscles of the same patient. In the chronic phase, there was a positive correlation between the degree of spontaneous activity in a muscle and the length of its axon (p less than .01) and a negative correlation between the amount of spontaneous activity and the degree of reflex activity (p less than .01). Specifically, the lower motor neuron in the chronic phase of an SCI seems to behave much like an axonopathy where the degree of spontaneous EMG activity is dependent on the length of the axon, with the additional concept that spontaneous activity is inhibited by spasticity.