According to the World Health Organization (WHO), neurodegenerative diseases (NDDs) are predicted to supersede cancer as the second leading cause of death by 2040. Conventional treatment modalities, including medications, physical, occupational, and speech therapies, assistive devices, and lifestyle adjustments, can help manage symptoms and slow down disease progression. However, it is critical to recognize that these treatments do not prevent or reverse disease progression. Current research aims to develop therapies that can modify the underlying degenerative processes and decelerate these conditions' progression. Traditional treatment options for neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington Disease (HD), have been largely unsuccessful. A key advancement in treating NDDs is the development of non-invasive drug delivery systems across the blood-brain barrier (BBB). The BBB, a unique, dynamic, and multifunctional interface formed by cerebral endothelial cells and their tight junctions, serving as the primary protection for the brain against pathogens, toxins, and other harmful elements. However, it also significantly obstructs the delivery of potent drugs during NDD treatment. According to statistics, 190 investigational new drugs have failed in clinical trials. Furthermore, a recent report by the Tufts Center for the Study of Drug Development indicates that central nervous system (CNS)-oriented drugs take 20% longer to develop and 38% longer to gain approval than non-CNS drugs.
Furthermore, with backing from public institutions, the introduction of new CNS small-molecule drugs to the market has surged. Small molecules, owing to attributes such as easy oral administration, permeability, tissue penetration, target specificity, and selective distribution, hold promise for treating NDDs. Polar drugs or highly charged molecules are commonly restricted from passing through the BBB due to the presence of tight junctions. Low molecular weight drugs are often desirable as they can diffuse through very narrow intercellular spaces. However, various significant CNS drugs that are active but large with non-conducive features are prevented from direct entry. Nevertheless, efflux transporters and receptor molecules at the BBB either aid or impede drug permeability. Thus, we propose small molecules as an alternative approach for modulating neurological diseases.
Leveraging their intrinsic benefits including oral administration, target specificity, and selective distribution, small molecules hold potential in treating NDDs, with the FDA's approval rate for CNS-focused drugs rising from 7% (2012–2018) to 16% (2019–2022). The BBB's changes during healthy aging alter drug transport dynamics, potentially impacting age-related illnesses' onset. Despite some adaptations serving positive functions, BBB integrity tends to decline with age, manifesting in markers of BBB collapse in animal models, exacerbated in the presence of NDDs. This proposal centres on understanding these changes, focusing on the mechanisms behind altered small molecule transport across the BBB, and alterations in ion channel and transporter dynamics due to aging.
Understanding these age-related alterations in BBB functions could provide valuable insights into the pathogenesis of neurodegeneration and inform the development of targeted therapeutic strategies to mitigate disease progression.
We encourage:
- Examination of transporter dynamics and receptor expression profiles in neurodegenerative disease models.
- Integration of in vivo imaging techniques to visualize BBB permeability and real-time small molecule transport.
- Examination of BBB disruption in AD and PD in small molecule drug therapeutic approaches.
- Study of BBB disruption associated with aging in neurological disorders.
- Examination of how iron transport dysfunction affects BBB integrity in neurological diseases.
- Study of how neuroinflammation impacts BBB dysfunction and integrity.
- Analysis of BBB permeability in Alzheimer’s disease.
- Investigation of neuroinflammation mechanisms in aging, particularly about AD, and their therapeutic approaches.
- Examination of how activated microglial cells and astrocytes influence small molecule transport across BBB dysfunctions and their molecular mechanisms
Keywords:
Small Molecule Transport, Blood-Brain Barrier, Neuroinflammation, Neurodegenerative Disorders, Transporter Dynamics
Important Note:
All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
According to the World Health Organization (WHO), neurodegenerative diseases (NDDs) are predicted to supersede cancer as the second leading cause of death by 2040. Conventional treatment modalities, including medications, physical, occupational, and speech therapies, assistive devices, and lifestyle adjustments, can help manage symptoms and slow down disease progression. However, it is critical to recognize that these treatments do not prevent or reverse disease progression. Current research aims to develop therapies that can modify the underlying degenerative processes and decelerate these conditions' progression. Traditional treatment options for neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington Disease (HD), have been largely unsuccessful. A key advancement in treating NDDs is the development of non-invasive drug delivery systems across the blood-brain barrier (BBB). The BBB, a unique, dynamic, and multifunctional interface formed by cerebral endothelial cells and their tight junctions, serving as the primary protection for the brain against pathogens, toxins, and other harmful elements. However, it also significantly obstructs the delivery of potent drugs during NDD treatment. According to statistics, 190 investigational new drugs have failed in clinical trials. Furthermore, a recent report by the Tufts Center for the Study of Drug Development indicates that central nervous system (CNS)-oriented drugs take 20% longer to develop and 38% longer to gain approval than non-CNS drugs.
Furthermore, with backing from public institutions, the introduction of new CNS small-molecule drugs to the market has surged. Small molecules, owing to attributes such as easy oral administration, permeability, tissue penetration, target specificity, and selective distribution, hold promise for treating NDDs. Polar drugs or highly charged molecules are commonly restricted from passing through the BBB due to the presence of tight junctions. Low molecular weight drugs are often desirable as they can diffuse through very narrow intercellular spaces. However, various significant CNS drugs that are active but large with non-conducive features are prevented from direct entry. Nevertheless, efflux transporters and receptor molecules at the BBB either aid or impede drug permeability. Thus, we propose small molecules as an alternative approach for modulating neurological diseases.
Leveraging their intrinsic benefits including oral administration, target specificity, and selective distribution, small molecules hold potential in treating NDDs, with the FDA's approval rate for CNS-focused drugs rising from 7% (2012–2018) to 16% (2019–2022). The BBB's changes during healthy aging alter drug transport dynamics, potentially impacting age-related illnesses' onset. Despite some adaptations serving positive functions, BBB integrity tends to decline with age, manifesting in markers of BBB collapse in animal models, exacerbated in the presence of NDDs. This proposal centres on understanding these changes, focusing on the mechanisms behind altered small molecule transport across the BBB, and alterations in ion channel and transporter dynamics due to aging.
Understanding these age-related alterations in BBB functions could provide valuable insights into the pathogenesis of neurodegeneration and inform the development of targeted therapeutic strategies to mitigate disease progression.
We encourage:
- Examination of transporter dynamics and receptor expression profiles in neurodegenerative disease models.
- Integration of in vivo imaging techniques to visualize BBB permeability and real-time small molecule transport.
- Examination of BBB disruption in AD and PD in small molecule drug therapeutic approaches.
- Study of BBB disruption associated with aging in neurological disorders.
- Examination of how iron transport dysfunction affects BBB integrity in neurological diseases.
- Study of how neuroinflammation impacts BBB dysfunction and integrity.
- Analysis of BBB permeability in Alzheimer’s disease.
- Investigation of neuroinflammation mechanisms in aging, particularly about AD, and their therapeutic approaches.
- Examination of how activated microglial cells and astrocytes influence small molecule transport across BBB dysfunctions and their molecular mechanisms
Keywords:
Small Molecule Transport, Blood-Brain Barrier, Neuroinflammation, Neurodegenerative Disorders, Transporter Dynamics
Important Note:
All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.