Microglial pathological synaptic pruning in epilepsy: pathophysiology and therapeutic potential.

Alzheimer’s disease (AD) constitutes the primary cause of dementia worldwide []. This neurodegenerative condition is clinically characterized by an array of cognitive dysfunctions, including progressive memory loss and spatiotemporal disorientation [,]. Associated with a highly complex etiology, AD can be familial or sporadic, with the latter accounting for the vast majority of diagnoses [,,]. At the molecular level, AD is characterized by the deposition of amyloid beta plaques and the accumulation of intraneuronal tangles of phosphorylated tau protein [,]. While disease-modifying therapies have gained well-deserved attention in recent years [], first-line treatments remain focused on symptom management, including N-methyl-D-aspartate receptor antagonists (e.g., memantine) and cholinesterase inhibitors [,,]. The latter includes, for instance, donepezil (DNPZ), a reversible inhibitor proven to enhance cognitive function in mild to severe cases of AD []. Despite its established therapeutic efficacy, DNPZ is associated with poor cerebral bioavailability, partly due to the limiting effects of brain barrier systems. Brain barriers, the designated guardians of the central nervous system (CNS), maintain brain homeostasis and include structures such as the blood–brain barrier and the blood–cerebrospinal fluid barrier (BCSFB). The BCSFB is composed of the ciliated epithelium of the choroid plexus (CP), resting upon a layer of loose connective tissue and a complex network of fenestrated capillaries [,]. Besides functioning as a physical and biochemical barrier, the CP is a region of bioactive compound synthesis and secretion, with the cerebrospinal fluid (CSF) as the structure’s main secretory product [,]. The pharmacological relevance of the BCSFB lies in its active role in regulating blood-to-CSF and CSF-to-blood compound trafficking. To such exchanges, contribute the membrane-transporting systems expressed in the BCSFB, including the solute carrier (SLC) and ATP-binding cassette (ABC)-type transporters [,,]. Nanotechnology emerges as a strategy in which the production of specialized delivery systems increases the cerebral bioavailability of diagnostic and therapeutic compounds, thereby surpassing biological barriers [,]. Due to the inherited versatility, biocompatibility, and biodegradability, chitosan (CS)-based nanoparticles (NPs) are amongst the most commonly used polymeric nanosystems [,]. CS-based and CS-coated NPs have been explored to enhance the biological performance of drugs used to treat AD, with very promising results [,,]. More recently, chronotherapy, an approach that explores the timed administration of drugs in accordance with an individual’s biological rhythms, has gained considerable attention in the field of personalized therapy [,]. Circadian rhythms (i.e., free-running endogenous rhythms with approximately 24-h periods) are crucial regulators of numerous physiological, metabolic, and behavioural processes in nearly all living organisms [,,]. Although generated by intrinsically autonomous machinery, endogenous rhythms are synchronized with the external environment via a range of environmental cues (e.g., light, temperature, food intake), commonly known as [,]. In mammals, the circadian system operates as a hierarchy, with a master clock in the suprachiasmatic nucleus of the hypothalamus synchronising secondary and tertiary structures [,,]. The presence of functional machinery driving cellular clockwork has been described in numerous tissues, including the CP []. Within the barrier, circadian rhythms influence CSF secretion and the expression of components of adherens junctions and membrane transporters, namely SLC and ABC-type systems [,,]. Thus, considering a chronotherapeutic approach, exploring BCSFB-associated rhythms may allow an increase in the cerebral bioavailability of numerous drugs.