Phototherapy for age-related brain diseases: Challenges, successes and future.

Brain diseases present a significant obstacle to both global health and economic progress, owing to their elusive pathogenesis and the limited effectiveness of pharmaceutical interventions. Phototherapy has emerged as a promising non-invasive therapeutic modality for addressing age-related brain disorders, including stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), among others. This review examines the recent progressions in phototherapeutic interventions. Firstly, the article elucidates the various wavelengths of visible light that possess the capability to penetrate the skin and skull, as well as the pathways of light stimulation, encompassing the eyes, skin, veins, and skull. Secondly, it deliberates on the molecular mechanisms of visible light on photosensitive proteins, within the context of brain disorders and other molecular pathways of light modulation. Lastly, the practical application of phototherapy in diverse clinical neurological disorders is indicated. Additionally, this review presents novel approaches that combine phototherapy and pharmacological interventions. Moreover, it outlines the limitations of phototherapeutics and proposes innovative strategies to improve the treatment of cerebral disorders.

New Insights into Alzheimer's Disease: Novel Pathogenesis, Drug Target and Delivery.

Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid ß protein (Aß) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aß and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aß cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aß aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aß- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aß-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aß assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.

New insight into brain disease therapy: nanomedicines-crossing blood-brain barrier and extracellular space for drug delivery.

INTRODUCTION: Brain diseases including brain tumor, Alzheimer's disease, Parkinson's disease, etc. are difficult to treat. The blood-brain barrier (BBB) is a major obstacle for drug delivery into the brain. Although nano-package and receptor-mediated delivery of nanomedicine markedly increases BBB penetration, it yet did not extensively improve clinical cure rate. Recently, brain extracellular space (ECS) and interstitial fluid (ISF) drainage in ECS have been found to determine whether a drug dissolved in ISF can reach its target cells. Notably, an increase in tortuosity of ECS associated with slower ISF drainage induced by the accumulated harmful substances, such as: amyloid-beta (Aß), α-synuclein, and metabolic wastes, causes drug delivery failure. AREAS COVERED: The methods of nano-package and receptor-mediated drug delivery and the penetration efficacy of nanomedicines across BBB and ECS are assessed. EXPERT OPINION: Invasive delivering drug via ECS and noninvasive near-infrared photo-sensitive nanomedicines may provide a promising benefit to patients with brain disease.