Natural Products from Plants and Algae: Comparison
Please note this is a comparison between Version 1 by Stephan Schilling and Version 3 by Vivi Li.

Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. 

  • Alzheimer’s disease
  • neurodegeneration
  • drug development
  • clinical studies

1. Introduction

Neurodegenerative diseases are a group of disorders in which neuronal function and survival are seriously affected. Many of these diseases, including Parkinson’s, Huntington’s and Alzheimer’s Disease (AD), are caused by structural changes and the deposition of proteins; therefore, they are also assigned to the group of protein misfolding diseases or amyloidoses [1][2][3][1,2,3]. AD is by far the most common cause of neurodegeneration and dementia. It is estimated that AD currently affects 55 million people worldwide (World-Alzheimer-Report-2021. Available online:, accessed on 4 February 2022). Characteristic symptoms of the disease are progressive memory loss, impaired cognitive function and paranoia. The histopathological hallmarks of AD, extracellular amyloid deposits (“amyloid plaques”), which mainly consist of the peptide Aβ, and intraneuronal neurofibrillary tangles of the hyperphosphorylated protein tau, mainly affect the cerebral cortex and the hippocampus [4][5][4,5]. Numerous studies suggest that the disease is initiated by the deposition of Aβ, which starts presumably years or decades before the first symptomatic changes [6]. The slow Aβ deposition triggers a downstream cascade (the amyloid cascade), which involves pathologic tau formation and hyperphosphorylation, widespread neuroinflammation and, finally, neuronal death [7][8][7,8]. Although the intense research during the last decades enabled a much better understanding of the crucial events in AD pathogenesis, a curative therapy that halts the progression of the disease is not yet available. Most of the so-called disease-modifying experimental drugs are targeting events of the amyloid cascade such as the generation and aggregation of Aβ and the phosphorylation of tau or the cellular metabolism and energy homeostasis [9]. The drug development in AD is faced with several challenges which has resulted in numerous setbacks in recent years [10]. For instance, the enzymes responsible for Aβ formation also have physiological substrates and functions. This complicates the suppression of amyloid peptide formation without interfering with other proteolytical degradation processes. Prominent examples are the γ-secretase complex and the β-secretase BACE1, which play a role in the formation of Aβ peptides [11][12][13][11,12,13]. Moreover, several reports suggest that Aβ1–40/42 and tau also have physiological functions, which leads one to question whether these represent druggable targets [14][15][16][17][14,15,16,17]. Also, many of the amyloidogenic proteins are localized in the cell nucleus or cytosol, which makes an effective suppression of the aggregation or the breakdown of the conglomerates, e.g., by antibodies, even more difficult [18]. Third, the efficient passage of the blood-brain barrier is needed and thus the pharmaceuticals are required to meet various physicochemical parameters [19][20][19,20]. Hence, methods are currently being examined (e.g., focused ultrasound) to make the blood-brain barrier more permeable [21].
Finally, major factors hampering the development and testing of new drugs are based on the clinical presentation of dementia and the currently available diagnostic biomarkers. AD patients frequently also show the presence of Lewy bodies and thus, significant pathological overlap with patients with dementia with Lewy bodies (DLB). As a result, the clinical testing of new active ingredients does not take place in “pure” Alzheimer’s patient populations. Accordingly, attempts are being made (using imaging methods and genetic analyses, among others) to conduct clinical studies in narrowly defined patient populations at an early stage of the disease [22][23][24][22,23,24]. Previously, numerous approaches were therefore undertaken in patients with a possibly too advanced a disease stage [23][25][23,25]. In addition, the available diagnostic biomarkers often do not specifically reflect the neurodegenerative disease or provide enough correlation with the clinical status of the patients. These imponderables could be responsible for the failure of different therapeutic approaches in the clinical phase. As mentioned above, alterations in biomarkers precede the symptoms of the disease [6][26][6,26], i.e., the measured value of a biomarker cannot be directly correlated with an effect on cognition. An example of this is the antibody bapineuzumab, which caused a significant change in phospho-tau in CSF in phase 2, but missed clinical endpoints [27].
All of these factors finally led to the numerous failures of disease-modifying drugs in AD clinical trials. The very recent accelerated approval of Aducanumab to treat AD may thus represent a first sign of success. However, the complexity also triggered the intense investigations of other fields, such as drugs from natural sources and nutraceuticals (Table 1). One potential reason is that food supplements may have the status as being generally regarded as safe (GRAS) and thus can be quickly applied in clinical testing, and eventually in combination with experimental drugs. Most of these substances are addressing protective mechanisms to cells by, e.g., anti-oxidative effects. However, there are also compounds in testing which are dedicated to disease-modification by, for example, their influence on immune cells. A prominent example is represented by oligomannate from red algae, which obtained approval for AD therapy in China and is currently being tested in additional clinical trials. Due to the emerging role in clinical testing, this rentry view focuses on the current treatment strategies which are based on natural products.  We will review drugs which are currently approved but will put a special emphasis on natural products from algae.