Attenuation of ALS progression during pregnancy—lessons to be learned or just a coincidence?

Hančević, Mirea; Bilić, Hrvoje; Sitaš, Barbara; Pavliša, Gordana; Borovečki, Fran; Munitić, Ivana; Bilić, Ervina

doi:10.1007/s10072-019-03748-z

Cited by 7 publications

(4 citation statements)

References 22 publications

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“…Aged microglia exhibit enhanced and prolonged proinflammatory response to LPS challenge, accompanied with fractalkine receptor (CX3CR1) downregulation, which makes them refractory to neuronal immunosuppressive cues, whereas the aged choroid plexus decreases leukocyte entry from the blood, which reduces its neuroprotective potential ( Godbout et al , 2005 ; Wynne et al , 2010 ; Baruch et al , 2014 ). Other environmental factors that may act as secondary hits or disease modifiers that could set off neurodegeneration include smoking, hormones, growth factors, head trauma, gut microbiome composition, peripheral nerve insults, and systemic and CNS inflammation ( Nguyen et al , 2004 ; Bilic et al , 2006 ; Chen et al , 2007 ; Erny et al , 2015 ; Hancevic et al , 2019 ; Schram et al , 2019 ; Zhan and Fang, 2019 ).…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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“…The few studies that evaluated the correlation between pregnancy or fertility and ALS progression have yielded contradictory results. Some case reports indicated rapid progression of ALS during pregnancy ( 7 , 10 , 25 , 26 ), while some argued that the patients were stable during the pregnancy and progressed rapidly after delivery ( 27 , 28 ). Therefore, we compared disease progression between sexes and in different subgroups based on temporal relationship between symptom onset and pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Fertility Does Not Alter Disease Progression in ALS Patients of Childbearing Age: A Three Centers Retrospective Analysis in Southern China

et al. 2022

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BackgroundLimited data exists on the clinical features of patients with amyotrophic lateral sclerosis (ALS) during reproductive ages.ObjectiveOur study characterized the clinical features of ALS and the effects of pregnancy on disease progression in patients with ALS.MethodsWe performed a retrospective study of female patients with ALS in three ALS research centers in southern China from 2009 to 2021. Data regarding fertility status, and clinical and genetic features, were collected. Age-matched male patients with ALS served as controls. The patients were divided into the following two subgroups: patients with symptom onset within 1 year of pregnancy and patients with symptom onset over 1 year group after pregnancy.ResultsA total of 52 female and 52 matched male patients were enrolled. There were no differences in female and male patients in the mean age of symptom onset, the mean baseline ALSFRS-R score, or median reduction of ALSFRS-R score (p > 0.05). The mean age of first pregnancy was 25.57 ± 4.40) years. The mean age of first pregnancy in the over 1 year group was lower than that in the within 1 year group (p= 0.01). There was no difference in the median reduction of ALSFRS-R between the two subgroups. In the univariate analysis, diagnostic delay was highly correlated with the disease progression, with short delay representing rapid progress. No multicollinearity was found among every variable. In addition, 40.38% patients carried ALS-related gene variants. The proportion with gene mutations in the within 1 year group was higher than that in the over 1 year group (p < 0.01). Furthermore, SETX was the most frequently mutated gene in this cohort (16.67%) including 4 uncertain mutation.ConclusionPregnancy and fertility were not associated with disease progression. Diagnostic delay was correlated with disease progression in this cohort. In addition, SETX might be a gene of concern for ALS patients of childbearing age.

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“…In addition, diagnosis is more frequent after menopause, and very few cases of pregnant women with ALS or pregnancies after the onset of the disease have been reported. On the rare occasion that the latter has occurred, pregnancy seems to have attenuated the symptoms of the pathology [ 83 ]. 17BE and T can also inhibit the activation of microglia cells, playing an anti-inflammatory role [ 84 , 85 ].…”

Section: Therapeutic Effect Of Dutasteridementioning

confidence: 99%

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently no medical cure, and riluzole and edaravone are the only two known approved drugs for treating this condition. However, they have limited efficacy, and hence there is a need to find new molecules. Dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase (5AR) enzymes, the therapeutic purposes of which, to date, are the treatment of benign prostatic hyperplasia and androgenic alopecia, shows great anti-ALS properties by the molecular-topology methodology. Based on this evidence, this review aims to assess the effects of dutasteride on testosterone (T), progesterone (PROG) and 17β-estradiol (17BE) as a therapeutic alternative for the clinical improvement of ALS, based on the hormonal, metabolic and molecular pathways related to the pathogenesis of the disease. According to the evidence found, dutasteride shows great neuroprotective, antioxidant and anti-inflammatory effects. It also appears effective against glutamate toxicity, and it is capable of restoring altered dopamine activity (DA). These effects are achieved both directly and through steroid hormones. Therefore, dutasteride seems to be a promising molecule for the treatment of ALS, although clinical studies are required for confirmation.

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Attenuation of ALS progression during pregnancy—lessons to be learned or just a coincidence?

Cited by 7 publications

References 22 publications

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Fertility Does Not Alter Disease Progression in ALS Patients of Childbearing Age: A Three Centers Retrospective Analysis in Southern China

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

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