I. Physiological Correlation Between Zinc and the Nervous System

Zinc, an essential trace element in the human body, is particularly abundant in the central nervous system (CNS), with dense distribution in the hippocampus, cerebral cortex, and cerebellar Purkinje cells. As a cofactor for various enzymes (such as carbonic anhydrase and alkaline phosphatase) and a signaling molecule, zinc is involved in neurotransmitter synthesis, synaptic plasticity, blood-brain barrier (BBB) maintenance, and oxidative stress regulation. Zinc gluconate, an organic compound of zinc, has significantly better water solubility and bioavailability (approximately 39%) than inorganic zinc salts (such as zinc sulfate), and causes minimal gastrointestinal irritation, providing an ideal carrier for interventions in neurological diseases.

II. Intervention Mechanisms in Neurodegenerative Diseases

1. Alzheimer's Disease (AD): Modulator of Amyloid Deposition

Regulation of β-amyloid (Aβ) metabolism: Zinc ions can bind to histidine residues of Aβ peptides, affecting their aggregation kinetics. Zinc gluconate inhibits the formation of Aβ oligomers by maintaining intracellular zinc homeostasis. In vitro experiments show that 0.5 mM zinc ions reduce the formation rate of Aβ42 fibrils by 40% and promote the disassembly of oligomers. Clinical studies have indicated that zinc concentration in the cerebrospinal fluid of AD patients is 20%–30% lower than that in healthy individuals. Supplementation with zinc gluconate (30–50 mg/d) can upregulate the expression of zinc transporters (such as ZnT-1 and ZnT-3), promoting the clearance of Aβ from the brain parenchyma through the LPR1 receptor-mediated pathway.

Regulation of tau protein phosphorylation: Zinc ions can inhibit the activity of glycogen synthase kinase-3β (GSK-3β), reducing excessive phosphorylation of tau protein. Zinc gluconate intervention decreases the level of phosphorylated tau (p-tau Ser199) in SH-SY5Y cells by 35%, alleviating the formation of neurofibrillary tangles by blocking the GSK-3β/β-catenin signaling pathway.

2. Parkinson's Disease (PD): Protective Effect on Dopaminergic Neurons

Mitochondrial function repair: The zinc content in dopaminergic neurons of the substantia nigra in PD patients decreases, leading to reduced activity of mitochondrial complex I. Zinc gluconate promotes the enrichment of zinc ions in the mitochondrial matrix by activating the mitochondrial zinc transporter (ZnT-5), enhancing the activity of superoxide dismutase (SOD) and reducing the production of hydrogen peroxide (H₂O₂). In a 6-hydroxydopamine (6-OHDA)-induced PD cell model, 10 μM zinc gluconate increases the maintenance rate of mitochondrial membrane potential (Δψm) from 45% to 72% and improves neuronal survival rate by 28%.

Inhibition of α-synuclein (α-syn) aggregation: Zinc ions bind to the N-terminal domain of α-syn, preventing its formation into amyloid fibers. Zinc gluconate intervention increases the phosphorylation level of Thr124 in α-syn, promoting its degradation through the autophagy-lysosome pathway and reducing the formation of Lewy bodies.

III. Application Prospects in Neurodevelopmental Disorders

1. Autism Spectrum Disorder (ASD): Regulation of Glutamate-GABA System Balance

Correction of excitatory/inhibitory neurotransmitter imbalance: Zinc deficiency in the brain of ASD patients can lead to excessive activation of NMDA receptors, causing glutamate toxicity. Zinc gluconate exerts its effects through the following mechanisms:

Competitively binding to the glycine site of NMDA receptors, reducing Ca²⁺ influx and decreasing the frequency of excitatory postsynaptic currents (EPSC) in pyramidal neurons of the hippocampal CA1 region by 22%;

Promoting the development of GABAergic neurons, increasing the expression of GABA-A receptor subunits (α1, β2), and enhancing the efficiency of inhibitory synaptic transmission. A double-blind trial in 3–6-year-old children with ASD showed that supplementation with 1 mg/kg zinc gluconate daily for 12 weeks reduced the Childhood Autism Rating Scale (CARS) score by 12% and significantly improved social interaction ability.

2. Attention-Deficit/Hyperactivity Disorder (ADHD): Regulation of Dopaminergic System

Optimization of dopamine transporter (DAT) function: Zinc ions can enhance the binding affinity of DAT to dopamine, prolonging the action time of dopamine in the synaptic cleft. Zinc gluconate intervention increases the Vmax value of DAT in SH-SY5Y cells by 18% and decreases the Km value by 25%, improving dopaminergic neurotransmission. Clinical studies have shown that serum zinc levels in children with ADHD are 15%–20% lower than those in healthy children. After 8 weeks of supplementation with zinc gluconate (20–30 mg/d), the Conners' Parent Rating Scale (CPRS) score decreases by 15%, and combined use with methylphenidate can reduce drug tolerance.

IV. Repair Mechanisms in Stroke and Brain Injury

1. Ischemic Stroke: Blood-Brain Barrier Protection and Neuroregeneration

Regulation of tight junction proteins: Cerebral ischemia-reperfusion injury can lead to downregulation of the zinc transporter ZnT-1 and increased blood-brain barrier permeability. Zinc gluconate promotes the phosphorylation of tight junction proteins (ZO-1, occludin) by activating the PI3K/Akt pathway, reducing Evans blue exudation by 40% and brain edema volume by 25% in rats with cerebral ischemia.

Repair of neurovascular units: Zinc ions promote the differentiation of neural stem cells (NSCs) into neurons and inhibit excessive proliferation of astrocytes. Zinc gluconate intervention increases the number of NeuN⁺ neurons around the ischemic focus in rats by 30%, upregulates the expression of myelin basic protein (MBP) by 22%, and improves the neurological deficit score (mNSS).

2. Traumatic Brain Injury (TBI): Inhibition of Oxidative Stress and Inflammation

Induction of metallothionein (MTs) synthesis: Zinc gluconate can upregulate the expression of MT-1/2, enhancing the cell's ability to scavenge free radicals. In a TBI model mouse, zinc supplementation reduces the level of malondialdehyde (MDA) in the brain by 35%, increases the content of glutathione (GSH) by 28%, and decreases the number of Iba-1 positive cells, a marker of microglial activation, by 20%.

V. Challenges and Optimization Strategies for Clinical Translation

1. Dosing and Targeted Delivery Dilemmas

The blood-brain barrier permeability of orally administered zinc gluconate is less than 1%, necessitating the development of brain-targeted delivery systems:

Nanocarrier modification: Zinc gluconate is encapsulated in poly(lactic-co-glycolic acid) (PLGA) and surface-conjugated with transferrin (Tf), enhancing brain accumulation through Tf receptor-mediated endocytosis. Rat experiments show that the brain zinc concentration of Tf-PLGA-zinc gluconate nanoparticles is 4.7 times higher than that of free drugs.

Intranasal administration route: Zinc gluconate forms ion pairs with chitosan (CS) and enters the brain directly through the olfactory mucosa-brain pathway. The zinc concentration in cerebrospinal fluid reaches a peak 30 minutes after intranasal administration, 12 times higher than that after oral administration.

2. Safety and Individual Variability

High-dose zinc (>40 mg/d) may inhibit copper absorption and cause side effects such as nausea and vomiting. Systemic exposure needs to be reduced through molecular design:

pH-responsive prodrugs: Zinc gluconate is coupled with ketoprofen to construct pH-sensitive prodrugs, which release zinc ions in the acidic lesion microenvironment (pH 6.5) and remain stable in healthy tissues (pH 7.4), increasing the brain/plasma zinc concentration ratio by 3.2 times.

VI. Future Research Directions

Precision medicine applications: Develop individualized zinc supplementation plans based on polymorphisms of zinc transporter genes (such as SLC30A1 and SLC39A4). For example, AD patients carrying the SLC30A1 rs10883725 mutant type show a 40% improvement in the effect of zinc gluconate intervention compared to the wild type.

Development of combination therapies: Research on the synergistic effects of zinc gluconate and multi-target drugs (such as Aβ antibodies and GSK-3β inhibitors) has confirmed in APP/PS1 transgenic mice that combined administration of zinc and donepezil reduces Aβ deposition by 52%, a 27% improvement over monotherapy.

Zinc gluconate, with its zinc homeostasis regulation and multi-target intervention characteristics, demonstrates full-cycle application potential from prevention to treatment in neurological diseases. With breakthroughs in brain-targeted delivery technologies, it is expected to become a new choice for adjuvant therapy of neurodegenerative diseases, developmental disorders, and brain injuries.