bims-drumid 2024-12-15 papers

Issue of 2024–12–15
five papers selected by
Volkmar Weissig, Midwestern University

Mitochondrion. 2024 Dec 09. pii: S1567-7249(24)00158-2. [Epub ahead of print] 102000

Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.

Nishad Keethedeth, Rajesh Anantha Shenoi.

Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.

Keywords: Blood brain barrier; Mitochondria targeting; Nanotherapeutics; Neurodegenerative diseases; Triphenyl Phosphonium

DOI: https://doi.org/10.1016/j.mito.2024.102000

Biochim Biophys Acta Mol Basis Dis. 2024 Dec 07. pii: S0925-4439(24)00611-2. [Epub ahead of print]1871(3): 167617

Mitochondria-targeting by small molecules against Alzheimer's disease: A mechanistic perspective.

Chinmay Pal.

Alzheimer's disease (AD) poses a considerable worldwide health obstacle, marked by gradual cognitive deterioration and neuronal loss. While the molecular mechanisms underlying AD pathology have been elucidated to some extent, therapeutic options remain limited. Mitochondrial dysfunction has become recognized as a significant factor in the development of AD, with oxidative stress and disrupted energy metabolism being critical elements. This review explores the mechanistic aspects of small molecule targeting of mitochondria as a potential therapeutic approach for AD. The review explores the role of mitochondrial dysfunction in AD, including its involvement in the accumulation of β-amyloid plaques and neurofibrillary tangles, synaptic dysfunction, and neuronal death. Furthermore, the effects of oxidative stress on mitochondrial function were investigated, including the resulting damage to mitochondrial components. Mitochondrial-targeted therapies have attracted attention for their potential to restore mitochondrial function and reduce AD pathology. The review outlines the latest preclinical and clinical evidence supporting the effectiveness of small molecules in targeting mitochondrial dysfunction in AD. Additionally, it discusses the molecular pathways involved in mitochondrial dysfunction and examines how small molecules can intervene to address these abnormalities. By providing a comprehensive overview of the latest research in this field, this review aims to shed light on the therapeutic potential of small molecule targeting of mitochondria in AD and stimulate further research in this promising area of drug development.

Keywords: Alzheimer's disease; Mitochondrial dysfunction; Oxidative stress; Reactive oxygen species; Small molecule

DOI: https://doi.org/10.1016/j.bbadis.2024.167617

Front Mol Neurosci. 2024 ;17 1516119

Regulation of adult neurogenesis: the crucial role of astrocytic mitochondria.

Danping Liu, Pei Guo, Yi Wang, Weihong Li.

Neurogenesis has emerged as a promising therapeutic approach for central nervous system disorders. The role of neuronal mitochondria in neurogenesis is well-studied, however, recent evidence underscores the critical role of astrocytic mitochondrial function in regulating neurogenesis and the underlying mechanisms remain incompletely understood. This review highlights the regulatory effects of astrocyte mitochondria on neurogenesis, focusing on metabolic support, calcium homeostasis, and the secretion of neurotrophic factors. The effect of astrocytic mitochondrial dysfunction in the pathophysiology and treatment strategies of Alzheimer's disease and depression is discussed. Greater attention is needed to investigate the mitochondrial autophagy, dynamics, biogenesis, and energy metabolism in neurogenesis. Targeting astrocyte mitochondria presents a potential therapeutic strategy for enhancing neural regeneration.

Keywords: Alzheimer’s disease; astrocytes; major depressive disorder; mitochondrial; neurogenesis

DOI: https://doi.org/10.3389/fnmol.2024.1516119

Expert Opin Drug Deliv. 2024 Dec 10. 1-16

Extracellular nanovesicles as neurotherapeutics for central nervous system disorders.

Naznin Bhom, Khonzisizwe Somandi, Poornima Ramburrun, Yahya E Choonara.

INTRODUCTION: The blood-brain barrier (BBB) is a highly selective structure that protects the central nervous system (CNS) while hindering the delivery of many therapeutic agents. This presents a major challenge in treating neurological disorders, such as multiple sclerosis, where effective drug delivery to the brain is crucial for improving patient outcomes. Innovative strategies are urgently needed to address this limitation.
AREAS COVERED: This review explores the potential of extracellular vesicles (EVs) as innovative drug delivery systems capable of crossing the BBB. EVs are membrane-bound vesicles derived from cells, tissues, or plant materials, offering natural biocompatibility and therapeutic potential. Recent studies investigating the permeability of EVs and their mechanisms for crossing the BBB, such as transcytosis, are summarized. Special emphasis is placed on plant-derived EVs (PDEVs) due to their unique advantages in drug delivery. Challenges related to the large-scale production and therapeutic consistency of EVs are also discussed.
EXPERT OPINION: EVs, particularly PDEVs, hold significant promise as scalable and noninvasive systems for CNS drug delivery. However, critical barriers such as improving standardization techniques, manufacturing processes and addressing scalability must be overcome to facilitate clinical translation. Collaborative efforts in research and innovation will be pivotal in realizing the therapeutic potential of EVs for neurological conditions.

Keywords: Blood brain barrier; central nervous system; extracellular vesicles; nanovesicles; plant-derived extracellular vesicles; transcytosis

DOI: https://doi.org/10.1080/17425247.2024.2440099

Neural Regen Res. 2024 Dec 07.

Exosomes in stroke management: a promising paradigm shift in stroke therapy.

Bo Wang, Pinzhen Chen, Wenyan Li, Zhi Chen.

Effective treatment methods for stroke, a common cerebrovascular disease with a high mortality rate, are still being sought. Exosome therapy, a form of acellular therapy, has demonstrated promising efficacy in various diseases in animal models; however, there is currently insufficient evidence to guide the clinical application of exosome in patients with stroke. This article reviews the progress of exosome applications in stroke treatment. It aims to elucidate the significant potential value of exosomes in stroke therapy and provide a reference for their clinical translation. At present, many studies on exosome-based therapies for stroke are actively underway. Regarding preclinical research, exosomes, as bioactive substances with diverse sources, currently favor stem cells as their origin. Due to their high plasticity, exosomes can be effectively modified through various physical, chemical, and genetic engineering methods to enhance their efficacy. In animal models of stroke, exosome therapy can reduce neuroinflammatory responses, alleviate oxidative stress damage, and inhibit programmed cell death. Additionally, exosomes can promote angiogenesis, repair and regenerate damaged white matter fiber bundles, and facilitate the migration and differentiation of neural stem cells, aiding the repair process. We also summarize new directions for the application of exosomes, specifically the exosome intervention through the ventricular-meningeal lymphatic system. The review findings suggest that the treatment paradigm for stroke is poised for transformation.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00665