Stephen Hawking – “Life would be tragic if it weren’t funny.”

By Paula Silva

What inspires me? LIFE. Today died Stephen Hawking, a man that truly inspire me with his life. Usually, I only post once a week, at Sundays, but today I need tribute Stephen Hawking with a post about amyotrophic lateral sclerosis (ALS). I was always fascinated by nervous system, maybe because it was the research area of one of my mentors, who I had the privilege of work with in Laboratory of Histology and Embryology (Institute of Biomedical Sciences Abel Salazar, University of Porto). Two years ago, inspired by Stephen Hawking and by Salvador Guedes, a man of wine world that also has ALS, I decided to explore the idea of developing a project with ALS and wine. The result was an application to a PhD grant. The student did not get the grant and left. Without student and money, the project was forgotten in a PC folder, until today when I heard about Stephen Hawking dead. 

As you know I am starting to explore a new scientific route, and I can assure you it is not easy an easy walk! But at the worst moments, quotes like "However difficult life may seem, there is always something you can do and succeed at. It matters that you don't just give up" and “Intelligence is the ability to adapt to change” inspire me to move on. Who told them? An inspiring man and scientist, Stephen Hawking .

Amyotrophic lateral sclerosis (ALS) is a fatal progressive degenerative disorder that affects lower motor neurons in brainstem and spinal cord, and the upper motor neurons in the motor cortex. Loss of these neurons leads to muscle atrophy and weakness, fasciculations and spasticity and currently no effective treatment is available. ALS exists in two forms: sporadic (SALS) with no known genetic component and familial (FALS) with a positive familial history and a genetic component. In 20 % of FALS, missense mutations have been identified in the gene coding for superoxide dismutase 1 (SOD1) (1), that lead to development of animal models of the disease. Various hypotheses were proposed to explain ALS pathophysiological mechanisms including protein aggregation (2), oxidative stress (3), mitochondrial dysfunction (4), excitotoxicity (5), and neuroinflammation (6). Neuroinflammation modulation has been proposed as an important mechanism for ALS (7). Indeed, the analysis of spinal cord tissue and cerebrospinal fluid from SALS and FALS cases revealed increased microglial activation and T cells infiltration, and higher concentration of proinflammatory mediators (8). Oxidative stress, has been proposed to be involved in ALS, being reported that malondialdehyde, hydroxynonenal, oxidised proteins, DNA and membrane phospholipids are elevated in ALS patients and in several model systems (3; 9-12). Polyphenols display antioxidant and anti-inflammatory properties (13). Red wine contains a polyphenols mixture that are responsible for health beneficial effects of moderate wine consumption, including in neurodegenerative diseases (14). The effects of wine polyphenols in ALS are only starting to be explored; nonetheless resveratrol and quercetin have been showing promising results. Resveratrol supplementation improves motor-neuron function and extends the lifespan of the SOD1G93A mouse model of ALS due to its antioxidant properties (15, 16). Resveratrol can increase the viability of a mutant SOD1-expressing cell line and can penetrate the central nervous system (17). Quercetin had an antioxidant effect in lymphoblast cell lines derived from patients with SOD1 linked FALS, and sporadic ALS (18). Given the wide spectrum of mechanisms involved in degeneration of motor neurons, combinatorial approaches represent the most promising strategy for preclinical assays, so the administration of a wine polyphenol extract could present synergistic/additive interactions. With this background my idea is to evaluate the synergistic/additive effects of wine polyphenols alone and in mixtures in the modulation of neuroinflammation and oxidative stress in ALS. Also, to correlate the inflammatory and oxidative stress markers of the SOD1G93A mice model with human ALS samples. Stephen Hawking liked a good glass of wine and champagne. Curiously, Michael Church, a Stephen Hawking friend, told that he noticed Stephen disease on a New Year’s Eve party, when he had difficulties filling a glass and that most of the wine ended up on the tablecloth. This incident aware him and other friends for ALS, and together tried to minimize the disturbances in Stephen life caused by ALS. Would not be interesting if wine polyphenols could help to minimize ALS effects. Do you think that this is nonsense correlation? No, again, I agree with Stephen “Life would be tragic if it weren’t funny”. Who wants to join me in this adventure?

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