Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice.
In transgenic mice overexpressing disease-causing human SOD1<sup>G37R</sup> or SOD1<sup>G93A</sup> mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration.
GCLM(-/-)/hSOD1<sup>WT</sup> mice developed overt motor symptoms (e.g. tremor, loss of extension reflex in hind-limbs, decreased grip strength and paralysis) characteristic of mice models over-expressing ALS-linked mutant hSOD1.
In addition, we have recently reported elevated heart rate and blood pressure in transgenic (TG) mice carrying the SOD1 mutant form of the human SOD1 transgene (SOD1-G93A) even prior to the appearance of motor symptoms.
The mice heterozygotic for the human mutated SOD1 (D and DF) showed distinct ALS-like motor symptoms, whereas the mice heterozygotic for the normal SOD1 (W and WF) mice did not.
After identification of the clinical onset in each female G93A mutant SOD1 transgenic mouse, we intraperitoneally administered multiple doses of edaravone to the mice and observed their motor symptoms.
Thus, alterations in body weight are present in ALS patients already decades before clinical manifestation of ALS, while weight loss precedes motor symptoms of several years and is associated with poor prognosis.
Our results from the SOD1 model suggest that dendritic and dendritic spine changes foreshadow and underpin the neuromotor phenotypes present in ALS and may contribute to the varied cognitive, executive function and extra-motor symptoms commonly seen in ALS patients.
Motor neurons of the spinal cord in transgenic mice with a FALS-linked mutant SOD1 also showed a marked increase of GRP78/BiP, an ER-resident chaperone, just before the onset of motor symptoms.