Blood pressure measurements in a transgenic SOD1-G93A mouse model of amyotrophic lateral sclerosis

Kandinov, Boris; Drory, Vivian E.; Tordjman, Karen; Korczyn, Amos D.

doi:10.3109/17482968.2012.662986

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…Further features of interest include creatine kinase, whose levels highly correlate with creatinine levels, suggested to be predictive of prognosis in ALS 42,43 . Pulse and blood pressure, which at first glance may be surprising predictive features for ALS, are supported by a body of literature suggesting sympathetic dysfunction in ALS [44][45][46][47] . Further research and studies are needed to assess the potential of these features and elucidate their involvement in ALS pathophysiology.…”

Section: Discussionmentioning

confidence: 64%

Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with substantial heterogeneity in its clinical presentation. This makes diagnosis and effective treatment difficult, so better tools for estimating disease progression are needed. Here, we report results from the DREAM-Phil Bowen ALS Prediction Prize4Life challenge. In this crowdsourcing competition, competitors developed algorithms for the prediction of disease progression of 1,822 ALS patients from standardized, anonymized phase 2/3 clinical trials. The two best algorithms outperformed a method designed by the challenge organizers as well as predictions by ALS clinicians. We estimate that using both winning algorithms in future trial designs could reduce the required number of patients by at least 20%. The DREAM-Phil Bowen ALS Prediction Prize4Life challenge also identified several potential nonstandard predictors of disease progression including uric acid, creatinine and surprisingly, blood pressure, shedding light on ALS pathobiology. This analysis reveals the potential of a crowdsourcing competition that uses clinical trial data for accelerating ALS research and development

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Section: Discussionmentioning

confidence: 64%

Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression

et al. 2014

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“…This effect is unlikely to be attributed to other activities of rilmenidine such as anti-hypertensive effects mediated by ADRA2/α2-adrenoceptor activation. Given that mutant SOD1 mice have elevated blood pressure [ 45 ], rilmenidine would normalize blood pressure which is unlikely to be detrimental. Next, activation of I 1 Rs by rilmenidine reduces cytoplasmic IP 3 levels thereby blocking Ca 2+ release from the ER [ 26 ], which would not promote motor neuron injury.…”

Section: Discussionmentioning

confidence: 99%

Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression

et al. 2017

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Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.

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“…The cardiovagal function was found to be impaired in up to 50% of ALS patients [ 241 ], more frequently in those with a low respiratory capacity [ 244 , 245 ]. Some studies have found an abnormally increased cardiovascular sympathetic tone in ALS patients [ 246 ] and SOD1 G93A mice [ 247 , 248 ], especially regarding alpha-sympathetic rather than beta-sympathetic hyperactivity. Additionally, there is increased activity of the norepinephrine transporter in cardiac sympathetic nerve terminals, which is indeed associated with shorter survival [ 249 ].…”

Section: Involvement Of the Autonomic Nervous System In Alsmentioning

confidence: 99%

Sensory Involvement in Amyotrophic Lateral Sclerosis

Rubio

Herrando-Grabulosa

Navarro

2022

IJMS

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Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean that their pathological significance is not relevant. In this review, we have made an extensive description of the involvement of sensory and autonomic systems described to date in ALS, from clinical, neurophysiological, neuroimaging, neuropathological, functional, and molecular perspectives.

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Blood pressure measurements in a transgenic SOD1-G93A mouse model of amyotrophic lateral sclerosis

Cited by 8 publications

References 30 publications

Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression

Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression

Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression

Sensory Involvement in Amyotrophic Lateral Sclerosis

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