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Biomedical subjects

Gerta Vrbová

Publications and source records attributed to Gerta Vrbová.

8 recordsLinked to original sources
PubMed2005

Spinal muscular atrophy: a delayed development hypothesis.

Spinal muscular atrophy is an inherited neuromuscular disorder. The gene responsible for the disease has been identified and named the SMN gene. This review is prompted by recent advances in understanding cellular function of the SMN gene and its gene product and by the increasing evidence that maturation of all parts of the neuromuscular system is delayed in spinal muscular atrophy patients. We suggest that the timing of developmental changes in motoneurons and muscles is critical for their survival. Delayed maturation of either motoneuron or muscle can cause these cells to die so the molecules that are involved in controlling their rate of maturation are crucial for normal development. We suggest that SMN gene/protein is one such molecule, because the neuromuscular system develops more slowly in spinal muscular atrophy patients, where SMN protein is absent, and in animals models, where SMN protein is reduced.

Child↗
PubMed2004

Function induced modifications of gene expression: an alternative approach to gene therapy of Duchenne muscular dystrophy.

In Duchenne muscular dystrophy a large gene that codes for dystrophin is altered. The possibility that the defective gene/protein could be at least in part substituted by other molecules that the diseased muscle is able to produce and that have a function similar to that of dystrophin is being discussed. Muscle fibres have a tremendous adaptive potential, and the expression of several protein isoforms can be induced by either stretch or long-term change of activity. The exploitation of this ability of muscle cells to express new genes, which would code for proteins that will not be alien to the individual, for treatment of Duchenne muscular dystrophy is being considered. The argument for this approach is strengthened by results that in patients with Duchenne muscular dystrophy the progress of the disease can be slowed with changes of muscle activity.

Biomechanical Phenomena↗
PubMed2003

Axotomized motoneurons can be rescued from cell death by peripheral nerve grafts: the effect of donor age.

Injury to neonatal nerves, unlike adult nerves, results in poor regeneration and extensive motoneuron death. We examined whether exposure to a more mature nerve environment could rescue axotomized motoneurons following neonatal injury. The sciatic nerve in 1 hindlimb of 3-day-old (P3) rats was transected and the cut end sutured to a nerve graft taken from donor rats, which ranged between P3 and P21. The extent of motoneuron survival and axon regeneration was established 7 days later. Since integrins play an important role in regeneration, we also examined the effect of manipulating integrin binding in nerve grafts. Following axotomy at P3 and implantation of nerve grafts from 3-day-old rats, approximately 38% of motoneurons survived. In contrast, grafts from rats aged 5 days and older resulted in an improvement in regeneration, and over 70% of motoneurons survived. This survival-promoting effect of P5 grafts was prevented by blocking beta1-integrins. In contrast, increasing beta1-integrin levels in grafts from P3 rats dramatically increased motoneuron survival. Thus, following neonatal nerve injury, exposure to a more mature nerve environment significantly increases motoneuron survival, an effect that is dependent upon beta1-integrin signaling. Therefore, pharmacological upregulation of beta1-integrins may significantly improve the outcome of neonatal nerve injuries.

Aging↗
PubMed2002

Pseudorabies virus-based gene delivery to rat embryonic spinal cord grafts.

The construction and application of recombinant pseudorabies viruses (PrVs) for the delivery of beta-galactosidase and/or green fluorescent protein (GFP) genes to rat embryonic spinal cord cells are reported here. These viruses were specifically designed to infect embryonic spinal cord neurons, which can be grafted into a lesioned spinal cord in order to restore the lost functions of the host cord. The recombinant viruses were constructed in two steps. The small subunit of the ribonucleotide reductase (RR) gene was first abolished by a frameshift mutation and an expression cassette containing the lacZ gene alone or together with the GFP gene was then inserted in place of the early protein 0 (EP0) gene of PrV. The reporter gene cassettes were positioned downstream from the PrV latency-associated promoter. Using an ex vivo system, we infected embryonic spinal cord explants with these viruses and found that neither vRREP0lac nor vRREP0lacgfp exerted any cytotoxic effect at all. It was also revealed that these viruses infect embryonic cells with high efficiency, and that infected neurons grafted into the spinal cord express the inserted reporter genes for periods of up to 12 weeks. This system offers a new approach for foreign gene transfer to neurons grafted into the CNS.

Animals↗
PubMed2002

Electromyographic activity patterns of ankle flexor and extensor muscles during spontaneous and L-DOPA-induced locomotion in freely moving neonatal rats.

In rats, hindlimb postural and locomotor functions mature during the first 3 postnatal weeks. Previous evidence indicates that maturation of descending monoaminergic pathways is important for the postnatal emergence of locomotion with adequate antigravity postural support. Here we have studied the effect of the monoamine precursor L-DOPA on locomotor activity in freely moving postnatal rats (7-9 days old) using electromyographic recordings from ankle extensor (soleus) and flexor (tibialis anterior or extensor digitorum longus) muscles. Before pharmacological treatment, both muscles were usually silent at rest, and during spontaneous movements there was a high degree of coactivation between the two antagonists. This was due to a longer electromyographic (EMG) burst duration in flexors, which partly overlapped with the extensor burst. L-DOPA administration (150 mg/kg) resulted in a marked increase in postural tonic EMG activity in extensors which appeared gradually within 10 min after injection and was sufficient for the pups to maintain a standing posture with the pelvis raised above ground. Thereafter, episodes of locomotion characterized by rhythmic reciprocal bursts of EMG activity in flexor and extensor muscles were seen. The L-DOPA-induced rhythmic EMG pattern was also seen in postnatal rats subjected to a midthoracic spinal cord transection, indicating that the effect of L-DOPA on motor coordination is exerted primarily at the level of the spinal pattern generator. Analysis of EMG burst characteristics showed that the pattern of L-DOPA-induced locomotion in both intact and spinalized postnatal rats resembled in some respects that observed in adults during spontaneous locomotion. The appearance of reciprocal activation during L-DOPA-induced locomotion in neonates was primarily due to a shortening of the EMG burst duration in flexors, which reduced the degree of antagonist coactivation. These results show that the spinal cord has the potential to produce coordinated overground locomotion several days before such movements are normally expressed in the freely moving animal.

Animals↗
PubMed2002

The effect of neonatal nerve injury on the expression of heat shock proteins in developing rat motoneurones.

The expression of the heat shock proteins hsp27 and hsp70 was examined in the spinal cord and sciatic nerves of developing rats. Using immunohistochemistry, we found that hsp27 is present in many motoneurones at birth. With development, the intensity of staining increases, reaching adult levels by 21 days, when all sciatic motoneurones express hsp27. In the sciatic nerve, hsp27 is strongly expressed throughout postnatal development. In contrast, hsp70 immunoreactivity in motoneurones and the sciatic nerve is weak at birth and does not change with development. The expression of heat shock proteins has been shown to increase in cells under conditions of stress, where they have beneficial effects on cell survival. The effect of neonatal nerve injury on hsp27 and hsp70 expression was also examined in this study. Four days after injury, staining for hsp27 increases in motoneurones, whereas hsp70 does not change. However, there is a significant increase in hsp70 staining in glial cells surrounding the injured motor pool, predominantly in astrocytes. Since neonatal nerve injury induces apoptotic motoneurone death, we also studied the co-expression of hsp27 with markers of apoptosis. No hsp27-positive motoneurones were found to be apoptotic, as assessed by both TUNEL and caspase-3 immunoreactivity. Therefore, it is possible that the upregulation of hsp27 observed in injured motoneurones may play a role in protecting motoneurones from apoptotic cell death following nerve injury.

Animals↗