PREFACE The advantages which have been derived from the caution with which hypothetical statements are admitted, are in no instance more obvious than in those sciences which more particularly belong to the healing art. It therefore is necessary, that some conciliatory explanation should be offered for the present publication: in which, it is acknowledged, that mere conjecture takes the place of experiment; and, that analogy is the substitute for anatomical examination, the only sure foundation for pathological knowledge. When, however, the nature of the subject, and the circumstances under which it has been here taken up, are considered, it is hoped that the offering of the following pages to the attention of the medical public, will not be severely censured. The disease, respecting which the present inquiry is made, is of a nature highly afflictive. Notwithstanding which, it has not yet obtained a place in the classification of nosologists; some have regarded its characteristic symptoms as distinct and different diseases, and others have given its name to diseases differing essentially from it; whilst the unhappy sufferer has considered it as an evil, from the domination of which he had no prospect of escape. The disease is of long duration: to connect, therefore, the symptoms which occur in its later stages with those which mark its commencement, requires a continuance of observation of the same case, or at least a correct history of its symptoms, even for several years. Of both these advantages the writer has had the opportunities of availing himself, and has hence been led particularly to observe several other cases in which the disease existed in different stages of its progress. By these repeated observations, he hoped that he had been led to a probable conjecture as to the nature of the malady, and that analogy had suggested such means as might be productive of relief, and perhaps even of cure, if employed before the disease had been too long established. He therefore considered it to be a duty to submit his opinions to the examination of others, even in their present state of immaturity and imperfection. To delay their publication did not, indeed, appear to be warrantable. The disease had escaped particular notice; and the task of ascertaining its nature and cause by anatomical investigation, did not seem likely to be taken up by those who, from their abilities and opportunities, were most likely to accomplish it. That these friends to humanity and medical science, who have already unveiled to us many of the morbid processes by which health and life is abridged, might be excited to extend their researches to this malady, was much desired; and it was hoped, that this might be procured by the publication of these remarks. Should the necessary information be thus obtained, the writer will repine at no censurewhich the precipitate publication of mere conjectural suggestions may incur: but shall think himself fully rewarded by having excited the attention of those, who may point out the most appropriate means of relieving a tedious and most distressing malady.

An Essay on the Shaking Palsy

Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms

Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders.

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Polyphenols: multipotent therapeutic agents in neurodegenerative diseases.

The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier.

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Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.

https://www.mdpi.com/1420-3049/25/22/5243/pdf

Important Flavonoids and Their Role as a Therapeutic Agent.

Reactive Oxygen Species are involved in the pathological development of many important human diseases such as neurodegenerative diseases, cardiovascular processes, diabetes and many others. The most promising strategy to prevent from the oxidative damage caused by these reactive species is the use of antioxidant molecules. These compounds can act as direct antioxidants through free radical scavenging mechanisms and/or as indirect antioxidants by enhancing the antioxidant status (enzymatic and non-enzymatic). Terpenes, one of the most extensive and varied structural compounds occurring in nature, display a wide range of biological and pharmacological activities. Here we highlight their antioxidant properties. Due to their antioxidant behaviour terpenes have been shown to provide relevant protection under oxidative stress conditions in different diseases including liver, renal, neurodegenerative and cardiovascular diseases, cancer, diabetes as well as in ageing processes. Evidence for this comes from the increasing number of publications on this issue in recent years. This review provides a complete overview of the natural terpenes with potential antioxidant properties, focusing on their source, structures, antioxidant mechanisms through which they exert their pharmacological and possible therapeutic activities.

Terpene Compounds in Nature: A Review of Their Potential Antioxidant Activity

Sideritis spp.: uses, chemical composition and pharmacological activities--a review.

Aloe vera has been traditionally used to treat skin injuries (burns, cuts, insect bites, and eczemas) and digestive problems because its anti-inflammatory, antimicrobial, and wound healing properties. Research on this medicinal plant has been aimed at validating traditional uses and deepening the mechanism of action, identifying the compounds responsible for these activities. The most investigated active compounds are aloe-emodin, aloin, aloesin, emodin, and acemannan. Likewise, new actions have been investigated for Aloe vera and its active compounds. This review provides an overview of current pharmacological studies (in vitro, in vivo, and clinical trials), written in English during the last six years (2014–2019). In particular, new pharmacological data research has shown that most studies refer to anti-cancer action, skin and digestive protective activity, and antimicrobial properties. Most recent works are in vitro and in vivo. Clinical trials have been conducted just with Aloe vera, but not with isolated compounds; therefore, it would be interesting to study the clinical effect of relevant metabolites in different human conditions and pathologies. The promising results of these studies in basic research encourage a greater number of clinical trials to test the clinical application of Aloe vera and its main compounds, particularly on bone protection, cancer, and diabetes.

https://www.mdpi.com/1420-3049/25/6/1324/pdf

Pharmacological Update Properties of Aloe Vera and its Major Active Constituents.

Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways; their most highlighted functions include cellular energy generation in the form of adenosine triphosphate (ATP), regulation of cellular calcium homeostasis, balance between ROS production and detoxification, mediation of apoptosis cell death, and synthesis and metabolism of various key molecules. Consistent evidence suggests that mitochondrial failure is associated with early events in the pathogenesis of ageing-related neurodegenerative disorders including Parkinson’s disease and Alzheimer’s disease. Mitochondria-targeted protective compounds that prevent or minimize mitochondrial dysfunction constitute potential therapeutic strategies in the prevention and treatment of these central nervous system diseases. This paper provides an overview of the involvement of mitochondrial dysfunction in Parkinson’s and Alzheimer’s diseases, with particular attention to in vitro and in vivo studies on promising endogenous and exogenous mitochondria-targeted protective compounds.

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Mitochondria-Targeted Protective Compounds in Parkinson's and Alzheimer's Diseases.

Parkinson’s disease is a chronic, multifactorial and progressive neurologic condition that affects around six million people worldwide, normally over 60 years of age, and is characterized by neurodegeneration of dopaminergic neurons in the substantia nigra. The species of the genus Panax, popularly named as “Ginseng”, are widely used as herbal remedies for their multiple beneficial effects, including their neurotherapeutic efficacies as protectors against major neurodegenerative diseases. The current review aims to report major findings and current knowledge on Ginseng and its major constituents as potential neuroprotective agents against Parkinson’s disease, focusing on its mechanisms of action and molecular targets. For that purpose, it includes all research works published in MEDLINE/PubMed within the last decade by utilizing the following combination of the keywords: “Ginseng, ginsenosides, neuroprotection and Parkinson’s disease”. As reported, most of the studies have been carried out on isolated compounds rather than extracts. The major ginsenosides investigated as neuroprotector agents for Parkinson’s disease are Rb1, Rg1, Rd and Re. Other minor components such as Notoginsenoside R2 and Pseudoginsenoside-F11 have also attracted remarkable interest as promising antiparkinson agents. These compounds exert their neuroprotective activity through different mechanisms including, among others, inhibition of oxidative stress and neuroinflammation, decrease in toxins-induced apoptosis and nigral iron levels, and regulation of N-methyl-D-aspartate receptor channel activity.

Elena González-Burgos

Papers

Terpene Compounds in Nature: A Review of Their Potential Antioxidant Activity

Sideritis spp.: uses, chemical composition and pharmacological activities--a review.

Pharmacological Update Properties of Aloe Vera and its Major Active Constituents.

Mitochondria-Targeted Protective Compounds in Parkinson's and Alzheimer's Diseases.

Potential Neuroprotective Activity of Ginseng in Parkinson’s Disease: A Review