Epilepsy, a extremely prevalent and complicated neurological dysfunction outlined by recurrent and unprovoked seizures, impacts roughly 70 million people globally [1]. Acute seizures in epilepsy sufferers can result in a sequence of extreme penalties, akin to mind harm, cognitive impairment, and even sudden surprising loss of life [2], [3]. Present therapeutic methods for acute epilepsy primarily depend on the administration of antiepileptic medicine (AEDs). Nevertheless, the tight junctions between endothelial cells throughout the extremely selective BBB limit the passive diffusion of most medicine, particularly these with excessive molecular weights or poor lipid solubility, leading to formidable obstacles on drug supply effectivity into brains and decreased therapeutic results for epilepsy [4], [5]. As well as, non-targeted high-dose systemic administration of AEDs regularly causes a variety of unintended effects, together with dizziness, cognitive deficits, and liver toxicity, in the end decreasing the treating efficacy as effectively [6]. Consequently, the power to trans-BBB and obtain efficient accumulation of therapeutic brokers in epileptic foci represents a vital problem and basic prerequisite for creating protected and environment friendly therapeutic methods for acute epilepsy.
Furthermore, neuronal synchronized hyperexcitability throughout epilepsy results in sustained excitotoxic neuronal harm, together with oxidative stress and neuroinflammation to drive a self-perpetuating cascade of pro-inflammatory cytokine launch, astrocyte/microglial proliferation, and ionotropic glutamate receptor (iGluR) hyperactivation [7], [8], [9]. These biochemical alterations will amplify pathological circuits and in the end exacerbate epileptogenesis, thus highlighting neurotransmitter homeostasis modulation and inflammatory regulation to an important place in epileptic remedies [10]. Rising proof means that focused dietary interventions could provide promising adjuvant therapeutic methods by addressing these twin pathological mechanisms [11], [12], [13]. Significantly noteworthy is pyridoxine (VB6), an important cofactor in over 140 enzymatic reactions, together with essential pathways concerned in neurotransmitter synthesis and immunomodulation, making it a promising therapeutic agent for assuaging epileptic signs by modulating each neurotransmitter synthesis and immune responses [14], [15], [16].
Lately, useful polymer-based nanosystems with built-in benefits of nanoscales, bioactivities and modifiability have emerged as promising nano-carries for trans-BBB drug supply when assembly the cruel microenvironment throughout epilepsy [17], [18]. Primarily, the floor properties of nanoparticles could be exactly engineered by way of particular focusing on molecules’ modifications to facilitate their selective binding to mobile receptors or floor antigens expressed on mind endothelial cells or neurons, thereby enhancing the specificity and effectivity of therapeutic drug supply to focus on mind areas [17], [19], [20], [21]. Particularly, an enzymatic shift inside seizure foci induces pathological L-tryptophan metabolism, creating a particular biochemical signature on endothelial cells that may be exploited for focused BBB binding and enhanced BBB penetrating, indicating a rational design of novel nanocarriers [22], [23], [24]. Moreover, polymer-based nanosystems geared up with stimuli-responsiveness are extremely adaptable to the physiological options of numerous ailments, enabling exact drug supply. Within the scenario of epileptic seizures, irregular electrical exercise in mind results in vital alterations within the native electrical microenvironment, making electrically responsive polymeric nanocarriers stand out within the remedy of acute epilepsy [25], [26]. Electro-responsive polymeric nanoparticles can reply to the modifications of electrical subject energy or potential upon publicity to irregular electrical alerts throughout seizures to set off the discharge of encapsulated medicine. This on-demand drug launch mechanism ensures correct drug supply to the seizure website, thereby rising native drug concentrations and enhancing therapeutic efficacy. Minimizing drug launch throughout non-seizure states can even scale back systemic unintended effects which are related to steady drug publicity. A number of methods have been utilized for establishing electrically responsive polymeric techniques, e.g. conductive polymer hydrogels counting on ion migration mechanisms and piezoelectric β-phase polyvinylidene fluoride techniques, though such approaches typically face challenges in reaching optimum biocompatibility [27], [28], [29]. Amongst these, polyelectrolyte complex-based supplies present probably the most satisfying comfort for building and biosafety for in-vivo software, presenting a possible strategy on designing surface-functionalized and electrically responsive polymeric nanocarriers for epileptic therapies.
Thus, on this work, we develop an electrostimulus-responsive polyelectrolyte complicated nanoparticle platform (HCT-Fu@VB6 NPs) consisted of three useful modules: hydroxypropylation and tryptophan functionalized chitosan conjugates (HCT), sulfated fucoidan (Fu), and small molecular drug VB6. The HCT-Fu@VB6 NP is engineered by way of one-step electrostatic self-assembly between HCT and Fu together with additional VB6 loading to handle the multidimensional challenges of acute epilepsy intervention (Fig. 1). HCT with L-type amino acid transporter 1 (LAT1)-targeting operate permits BBB penetration by way of LAT1 receptor-mediated transport whereas facilitates epileptogenic focus accumulation through transcytosis [30]. The included polysaccharide Fu features by way of a twin antioxidant/anti-inflammatory axis, neutralizing seizure-induced ROS overproduction whereas suppressing neuroinflammatory cascades [31]. Complementarily, as a coenzyme for neurotransmitter synthesis and a P2X7 receptor antagonist, VB6 alleviates epileptic signs by attenuating glutamate excitotoxicity and counteracting hypoxia-driven extracellular ATP overload [32], [33], [34], [35]. This tripartite therapeutic platform demonstrates three distinctive deserves: (1) Correct focusing on for BBB traversal and lesion-enhanced accumulation; (2) Pathological potential-responsive drug launch triggered by epileptic discharge-induced electrical microenvironment modifications; (3) Synergistic multi-mechanism intervention addressing oxidative stress, neuroinflammation, and excitatory/inhibitory imbalance. By converging stimulus-responsive supply with multi-target neuromodulation, this nanosystem establishes an possibility for precision epilepsy therapeutics that transcends standard mono-mechanistic approaches.
