Sexual dimorphism in disease onset and progression of a rat model of ALS

Suzuki, Masatoshi; Tork, Craig; Shelley, Brandon; McHugh, Jacalyn; Wallace, Kyle; Klein, Sandra; Lindstrom, Mary J.; Svendsen, Clive N.

doi:10.1080/17482960600982447

Cited by 64 publications

(62 citation statements)

References 22 publications

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“…For example, studies with untreated mutant SOD1 mice [31] and rats [52], including results from the present study, demonstrate that disease onset and overall survival occur earlier on average in males. In response to an exercise regimen therapy, delayed disease onset and survival was noted in only female mice [55], while AAV2 IGF-1 promoted benefit selectively in males in the present study.…”

Section: Sex-specific Effectssupporting

confidence: 54%

“…Sex-specific differences in disease onset and progression [31,40,52,55] and response to therapeutic interventions [16] have been noted in CNS disorders, including ALS. For example, studies with untreated mutant SOD1 mice [31] and rats [52], including results from the present study, demonstrate that disease onset and overall survival occur earlier on average in males.…”

Section: Sex-specific Effectsmentioning

confidence: 99%

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Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Lepore

Haenggeli

Gasmi³

et al. 2007

Brain Research

113

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The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1, and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1 G93A mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.

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Section: Sex-specific Effectssupporting

confidence: 54%

Section: Sex-specific Effectsmentioning

confidence: 99%

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Lepore

Haenggeli

Gasmi³

et al. 2007

Brain Research

113

View full text Add to dashboard Cite

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“…G93A rats, with males having an earlier disease onset than females (24). In our hands, male rats also demonstrated a more consistent disease phenotype (data not shown), as a result of which we only examined male animals.…”

Section: Animalsmentioning

confidence: 54%

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff¹,

Costantini²,

Crane

et al. 2008

The Journal of Immunology

141

177

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Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1G93A transgenic rats). With end-stage disease, SOD1G93A rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.

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“…Glial-derived neurotrophic factor dent models of ALS that mimic human disease with comparable progressive motor dysfunction and respira-(GDNF)-producing human cortical neural precursors spinally grafted to G93A rats significantly improved tory failure (17,23). motoneuron survival (30). However, cell graft survival the ventral horn (distance from the dorsal surface of the spinal cord at L3 level: 1.1-1.2 mm) (16).…”

Section: Introductionmentioning

confidence: 99%

“…Derivation of the Spinal hSSCs (30) and Klein et al (19) both reported poor graft survival with cyclosporin A immunosuppression after spiHuman SSCs were prepared from the cervical-upper thoracic region of spinal cord tissue obtained from a sinnal grafting of human neural progenitors in the G93A rat. Other studies, while reporting positive functional gle 8-week human fetus after an elective abortion.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Immunosuppressive Therapy for Spinal Grafting of Human Spinal Stem Cells in a Rat Model of ALS

et al. 2011

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Previous rodent studies employing monotherapy or combined immunosuppressive regimens have demonstrated a variable degree of spinal xenograft survival in several spinal neurodegenerative models including spinal ischemia, trauma, or amyotrophic lateral sclerosis (ALS). Accordingly, the characterization of optimal immunosuppressive protocols for the specific neurodegenerative model is critical to ensure reliable assessment of potential long-term therapeutic effects associated with cell replacement. In the present study we characterized the survival of human spinal stem cells when grafted into the lumbar spinal cords of a rodent model of ALS, SOD1 (G93A) male and female rats (60-67 days old). Four different immunosuppressive protocols were studied: i) FK506 (q12h); ii) FK506 (qd) + mycophenolate (PO; q12h, up to 7 days postop); iii) FK506 (qd) + mycophenolate (IP; q12h, up to 7 days postop); and iv) FK506 (qd) + mycophenolate (IP; qd, up to 7 days postop). Three weeks after cell grafting the number of surviving human cells was then systematically assessed. The highest density of grafted cells was seen in animals treated with FK506 (qd) and mycophenolate (IP; qd; an average 915 ± 95 grafted cells per spinal cord section). The majority of hNUMA-positive cells colocalized with doublecortin (DCX) immunoreactivity. DCX-positive neurons showed extensive axodendritic sprouting toward surrounding host neurons. In addition, migrating grafted cells were identified up to 500 µm from the graft. In animals treated with FK506 (q12h), FK506 (qd) + mycophenolate (PO; q12h) or FK506 (qd) + mycophenolate (IP; q12h), 11.8 ± 3.4%, 61.2 ± 7.8%, and 99.4 ± 8.9% [expressed as percent of the FK506 (qd) and mycophenolate (IP; qd)] cell survival was seen, respectively. In contrast to animals treated with a combination of FK506 + mycophenolate, robust CD4/8 immunoreactivity was identified in the vicinity of the injection tract in animals treated with FK506 only. These data suggest that a combined, systemically delivered immunosuppression regimen including FK506 and mycophenolate can significantly improve survival of human spinal stem cells after intraspinal transplantation in SOD1 (G93A) rats.Key words: Amyotrophic lateral sclerosis (ALS); Superoxide dismutase 1 (SOD1); Human spinal stem cells; FK506; Mycophenolate INTRODUCTIONDespite the discovery of several putative mechanisms underlying the onset and progression of ALS, there are no therapeutic strategies that successfully modify disAmyotrophic lateral sclerosis (ALS) is a lethal neuromuscular disease characterized by progressive degeneraease progression or outcome (33). Recently, cell-based therapies have emerged as potential treatments for sevtion of upper and lower motor neurons and corresponding motor and respiratory dysfunction. Approximately eral neurological disorders including ALS (18,28). For example, Xu et al. (34) reported that spinal grafting of 10% of patients have an inherited form of the disease, and of these 20% carry a mutation in the superoxide human spinal stem cells (h...

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Sexual dimorphism in disease onset and progression of a rat model of ALS

Cited by 64 publications

References 22 publications

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Optimization of Immunosuppressive Therapy for Spinal Grafting of Human Spinal Stem Cells in a Rat Model of ALS

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