Abstracts presented on 14th Meeting of the European
Neurological Society – Spain
June, 2004
Effect
of treatment with PDTC and IRFI 042 on strength and fatigue in MDX mice
S. Messina, P. Seminara, M. Aguennouz, M.C. Monici, H. Marini, F. Squadrito, G. Vita (Messina, I)
Previous studies provided
evidences that generation of reactive oxygen species and activation of
transcription factor NF-kB may play important roles in the pathogenesis of
Duchenne muscular dystrophy. We tested whether IRFI 042, a vitamin E-like
antioxidant, and PDTC, a NF-kB inhibitor, could have an effect on muscle
weakness in mdx mice. We treated 48 5/6-week old mdx and wild type mice with
intraperitoneal injections of PDTC (50 mg/kg), IRFI 042 (20 mg/kg), or vehicle,
three times a week for five weeks. Data regarding weight, survival and forelimb
strength and fatigue were collected. Motor performance measurements were
carried out using a grip meter attached to a force transducer which measures
peak force generated. Mdx mice treated with IRFI 042 or PDTC showed at the end
of treatment a significantly higher forelimb strength than vehicle controls
(IRFI 042: +53.6%, p<0.001; PDTC: +53.1%, p<0.05) as well as higher
strength normalised to weight (IRFI 042: +57.8%, p<0.001; PDTC: +54%,
p<0.05). Furthermore PDTC-treated mdx mice had significantly less fatigue
than vehicle animals (-120%, p<0.004).
Our results suggest that PDTC and
IRFI 042 might have a beneficial effect on weakness and fatigue in mdx mice.
Further studies are needed to investigate the morphological and biochemical
substrates of such encouraging preliminary results.
F. Chretien, P.A. Dreyfus, P. Caramelle, B. Chazaud, R.K. Gherardi (Créteil, F)
We have previously developed a murine model of bone marrow (BM) transplantation from B6-TgGFP transgenic mice to normal irradiated B6 mice, the cytoplasmic green fluorescent protein (GFP) being used as an unambiguous marker of donor-derived cells in host muscle. Using this model we were able to demonstrate that stem cell marker-expressing cells found in connective tissue and myogenic precursor cells (satellite cells) may be derived from bone-marrow in adulthood. To investigate the therapeutic potential of BM transplantation in muscle diseases such as dystrophinopathies, we compared the results obtained in C57Bl6 (B6) mice and mdx mice, a model for Duchenne muscular dystrophy in which muscle regeneration is dramatically increased. In mdx muscle compared to B6 muscle, we observed numerous GFP+ mononucleated cells corresponding to macrophages and numerous necrotic fibers filled by GFP+ macrophages and myoblasts. The number of GFP+ satellite cells number was similar in mdx and B6 mice 6 months post transplantation. However, GFP+ muscle fibers were more numerous in mdx mice. They were from month 1 post transplantation, a time point showing no GFP+ fiber in B6 mice. Six months post transplantation, 4 fold more GFP+ muscle fibers were found in mdx mice compared to B6 mice.
In contrast, dystrophin
expression was only mildly increased (0,65% at month 6) and colocalizations
between GFP and dystrophin was rarely found on serial cross sections. We
conclude that the nuclear domain of dystrophin is probably much shorter than
that of GFP.
F. Civati, M. Guglieri, M.G. D' Angelo, A. Tavano, F. Fabbro, M.L. Lorusso, M. Sironi, A.C. Turconi, G.P. Comi, N. Bresolin (Bosisio Parini, San Vito, Milan, I)
Background: Duchenne Muscular
Dystrophy (DMD) is a fatal recessive x-linked muscular disease caused by the
absence of dystrophin. Dystrophin isoforms are also expressed in the cerebral
neocortex and in the cerebellum. Cognitive impairment is described in 1/3 of
DMD patients, particularly in patients carrying deletions in the distal part of
the gene. Difficulties in verbal skills and reading abilities are more
frequently described in English speaking patients. According to the literature
children with DMD show linguistic deficits already in the early phases of
language development which mainly consist of poor expressive verbal abilities
and deficits in short-term memory. These observations suggest that in some
cases dystrophinopathy may be associated to language disorders. Preliminary
results in our group of Italian speaking children showed deficit in Grammatical
and Syntax Comprehension.
Aims of the study are:
1) to describe the language and reading ability in a group of italian DMD
children
2) to clarify the nature of the language and reading deficits
Patients: 13 children with DMD (mean age 8,3 years; standard deviation 1,7)
were diagnosed according to international standard criteria. Full Intelligence
Quotient(assessed using Wechsler Intelligence Scale) was >70.
Methods: Language and Reading abilities were determined through: “Test dello sviluppo Morfosintattico”, Battery of standardized tests, Battery to evaluate Dyslexia and Dysortography and Tasks of correctness and rapidity. To exclude additional cognitive deficits we evaluated attention/executive functions domain and memory and learning domain thought a Developmental Neuropsychological Assessment (NEPSY particularly: Auditory attention and response set - Visual attention - List learning - Memory for names).
Results: 8 patients out of 13
showed deficit in Syntax Comprehension. 7 patients out of 13 manifested
deficits in Grammatical Comprehension. No DMD patients (except one) presented
disabilities in reading. Most of the patients showed mild attention and memory
deficits.
Discussion: An early identification of the language and eventually
attention/memory difficulties, would be important for an early treatment, to
support DMD children in their learning course.