A dive into the untapped potential of marine compounds in counteracting neurodegeneration

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Parkinson’s Disease May Have Link to Stroke March 2017 

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018  

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A dive into the untapped potential of marine compounds in counteracting neurodegeneration

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Abstract

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms – including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.

Introduction

Neurodegenerative diseases (ND) are characterized by a gradual breakdown and eventual loss of synapses and neurons, primarily linked to the accumulation of pathologically altered proteins within the human brain and spinal cord. The specific functional systems affected vary among distinct neurological disorders, resulting in a diverse array of clinical manifestations. With the rise in life expectancy, there is a corresponding increase in the prevalence of such diseases. This growing trend not only intensifies the impact of these conditions on the patients' quality of life but also imposes a heavier burden on healthcare systems globally (Kovacs, 2017, Kovacs, 2019).

The most common neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). AD is the most prevalent neurodegenerative condition and the leading cause of dementia (Abeysinghe et al., 2020). The prevalence of this disease increases with age, rising from 1% in individuals aged 65–69 years, to 30% in those over 85 years old (“2023 Alzheimer's disease facts and figures, 2023”). As such, age is considered the main risk factor for AD (Richard, 2019). It is estimated that more than 100 million people worldwide will be affected by this disease by the year 2050 (Monteiro et al., 2023). Some cases of AD involve genetic predisposition, with mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2) and Apolipoprotein E (APOE) ε4 being the most commonly reported (Reitz, 2015).

PD is a complex neurodegenerative disease characterized by the early and significant death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Simon et al., 2020). PD incidence is of 20 per 100,000 new cases annually and also increases with age, rising 5- to 10-fold from the sixth to the ninth decades of life. Mutations on the genes coding for synuclein alpha gene (SNCA), Leucine-rich repeat kinase 2 (LRRK2), Parkin, PINK1 and DJ-1 are correlated with the onset of this disease (Blauwendraat et al., 2020). The clinical manifestations of PD comprise four main symptoms: tremor, bradykinesia, rigidity, and postural instability (Jagadeesan et al., 2017).

ALS is a neurodegenerative disorder characterized by the selective dysfunction and degeneration of motor neurons in the cortex, brainstem, and spinal cord. A hallmark of ALS pathology is the aggregation and accumulation of ubiquitinated proteinaceous inclusions, which contribute to progressive motor impairment ultimately leading to paralysis, respiratory failure, and death (Masrori & Van Damme, 2020; ). ALS has an annual incidence rate of approximately 1.2 to 6 cases per 100,000 individuals (Talbott et al., 2016). While most cases of ALS occur sporadically without a familial history, approximately 10% of cases involve dominantly inherited autosomal mutations in specific genes such as the genes coding for superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and C9orf72 (Saberi et al., 2015). The primary symptoms include progressive muscle weakness, slowed movements accompanied by muscle atrophy, muscle stiffness, and muscle cramps (Masrori & Van Damme, 2020).

MS is a chronic inflammatory and demyelinating condition impacting approximately 35.9 cases per 100,000 individuals (Leray et al., 2016; Walton et al., 2020). The impairment in oligodendrocyte regeneration and subsequent myelin damage contribute to axonal degeneration, serving as the primary driver for the irreversible neuronal loss that culminates in permanent disability (Yeung et al., 2019). Symptoms commonly observed in patients encompass walking difficulties, weakness, cognitive decline, fatigue and depression (Zwibel, 2009).

Neurodegenerative diseases are characterized by a complex etiology, involving a wide range of pathophysiological mechanisms that are often not fully understood. Nevertheless, several mechanisms are shared across them, namely pathological protein aggregation, synaptic and neuronal network defects, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation and neuronal cell death (Wilson et al., 2023). In more detail, neuroinflammation, oxidative stress, mitochondrial dysfunction, protein misfolding and accumulation, metal dysregulation and ferroptosis, among others, are well studied and described, being explored in this work (Fig. 1; for more detail information, see section 3) (Jellinger, 2010).

The currently available pharmacological therapies for neurodegenerative diseases are mainly focused on symptom relief, rather than stopping or slowing disease progression. For example, the use of cholinesterase inhibitors or N-methyl-d-aspartate (NMDA) receptor antagonists in AD can only temporarily improve cognitive function and has no effect on disease progression. Likewise, the use of levodopa, monoamine oxidase B (MAO-B) inhibitors, and/or catechol-O-methyltransferase (COMT) inhibitors on PD only alleviates motor symptoms, becomes less effective over time, and does not address the underlying neuronal loss. Consequently, the development of new therapeutic strategies that interfere with disease progression is an urgent need (Szeto & Lewis, 2016).

Marine compounds have demonstrated protective effects against several pathophysiological mechanisms' characteristic of neurodegenerative diseases. In fact, these compounds demonstrate a wide range of properties, including antioxidant, analgesic, immune-modulatory, antithrombotic, anticoagulant, anti-inflammatory, antiproliferative, antihypertensive, anti-diabetic, and cardioprotective effects (Suleria et al., 2016). The growing interest in biocompounds derived from marine sources is supported by their unique structural and chemical properties, which differ from those typically found in terrestrial sources. Numerous marine molecules exhibit significantly higher bioactivity (such as antioxidant, and anti-inflammatory effects, among others), often up to ten times greater than their terrestrial counterparts (Carson & Clarke, 2018). Despite their notable advantages, marine-derived compounds face limitations in availability from original sources and possess intricate chemical structures, challenging their synthesis (Martins et al., 2020). Nevertheless, pharmacological research continues to demonstrate the potential of marine-derived compounds in biomedicine, particularly in the context of neurodegeneration.

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