The neuroprotective effect of L-valine derivatives

As an essential branched-chain amino acid in humans, L-valine and its metabolites, along with chemically modified derivatives, exhibit unique potential in regulating central nervous system (CNS) functions. Research on their roles in improving abnormal neurobehavior (such as aggressive behavior) and exerting neuroprotective effects has attracted significant attention. In mouse models of aggressive behavior, L-valine derivatives intervene in abnormal behavior and provide neuroprotection by regulating neurotransmitter balance, inhibiting neuroinflammation, and repairing neuronal damage. Their mechanisms of action can be analyzed at the following levels:

I. Regulatory Effects of L-Valine Derivatives on Neurotransmitter Systems

The occurrence of aggressive behavior is closely linked to imbalances in neurotransmitters such as serotonin (5-HT), dopamine (DA), and γ-aminobutyric acid (GABA) in the CNS. L-valine derivatives reshape the homeostasis of neurotransmitter networks by influencing 递质 synthesis, release, or receptor sensitivity:

Activation of the serotonin system: Impaired 5-HT function is a classic biological marker of aggressive behavior. Certain derivatives of L-valine, such as N-acetyl-L-valine, enhance the activity of tryptophan hydroxylase (TPH), promoting the conversion of the 5-HT precursor tryptophan to 5-HT. In male mouse aggression models, intraperitoneal injection of N-acetyl-L-valine (100 mg/kg) increases hypothalamic 5-HT levels by 30%-40% while downregulating the expression of the 5-HT transporter (SERT), reducing 5-HT reuptake and prolonging its action time in the synaptic cleft, thereby inhibiting the transmission of aggressive impulses.

Balanced regulation of the dopamine system: Excessive dopamine release in the mesolimbic system enhances the rewarding effects of aggressive behavior. Derivatives like L-valine methyl ester inhibit the activity of the dopamine transporter (DAT), slowing dopamine clearance to avoid sharp fluctuations in the synaptic cleft. Studies show that this derivative maintains nucleus accumbens dopamine concentrations in model mice at 80%-90% of normal levels, preventing both motivational deficits from low levels and heightened impulsivity from excessive levels.

Enhanced GABAergic inhibition: As the primary inhibitory neurotransmitter in the CNS, reduced GABA receptor function leads to excessive neuronal excitation, exacerbating aggression. Hydroxyl-modified derivatives of L-valine, such as 3-hydroxy-L-valine, allosterically modulate GABAA receptors, enhancing chloride ion influx and strengthening postsynaptic inhibitory effects. In mouse open-field aggression tests, this derivative prolongs the attack latency by 2-3 fold and reduces attack frequency by over 50%. Its effects are dose-dependently antagonized by GABAA receptor antagonists (e.g., bicuculline), confirming its action through the GABA system.

II. Protective Mechanisms via Inhibiting Neuroinflammation and Oxidative Stress

Chronic stress or excessive neuronal activation associated with long-term aggressive behavior induces central neuroinflammation. L-valine derivatives alleviate neurodegenerative changes by inhibiting microglial overactivation and oxidative stress damage:

Maintaining microglial homeostasis: Abnormal activation of microglia in the prefrontal cortex and hippocampus of aggressive model mice releases pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), causing neuronal synaptic damage. Amide derivatives of L-valine, such as the L-valine-L-glutamine dipeptide, reduce pro-inflammatory factor transcription and release by inhibiting NF-κB pathway activation. Experiments show that after intervention with this derivative, hippocampal IL-6 levels in model mice decrease by 40%-50%, and microglia transition from an "amoeboid" activated form to a resting "ramified" form，indicating alleviated neuroinflammation.

Mitigating oxidative stress damage: Repeated neural excitation related to aggressive behavior triggers mitochondrial dysfunction, leading to reactive oxygen species (ROS) accumulation and lipid peroxidation. Thio-derivatives of L-valine, such as S-methyl-L-valine, enhance glutathione (GSH) synthetase activity, increasing brain GSH levels and scavenging excess ROS. In mouse brain homogenate assays, this derivative reduces malondialdehyde (MDA, a marker of lipid peroxidation) content by 25%-35% and increases superoxide dismutase (SOD) activity by over 30%, demonstrating its role in protecting neurons from oxidative damage by strengthening antioxidant systems.

III. Repairing Neuronal Structure and Synaptic Plasticity

Mice models of aggressive behavior often exhibit neuronal atrophy and reduced synaptic connections in brain regions such as the prefrontal cortex and hippocampus. L-valine derivatives improve neural circuit function by promoting neurotrophic factor expression and synaptic structure repair:

Upregulating neurotrophic factors: Brain-derived neurotrophic factor (BDNF), a key factor in maintaining neuronal survival and promoting synaptogenesis, has reduced expression linked to aggression. Ester derivatives of L-valine, such as L-valine ethyl ester, activate the cAMP response element-binding protein (CREB) signaling pathway, promoting BDNF gene transcription and translation. In the hippocampal CA1 region of mice, BDNF protein levels increase by 50%-60% after intervention with this derivative, accompanied by a ~1.5-fold increase in dendritic spine density, indicating enhanced neuronal synaptic plasticity.

Protecting and repairing synaptic structures: Aggressive model mice show thinning of the postsynaptic density (PSD) and widened synaptic clefts in the prefrontal cortex, reducing neural signal transmission efficiency. Hydroxylated derivatives of L-valine stabilize microtubule protein polymerization, maintaining the structural integrity of neuronal axons and dendrites, and promote the expression of synaptic adhesion molecules (e.g., nectin-3) to enhance synaptic connection stability. Electron microscopy shows that after derivative treatment, synaptic cleft width in model mice recovers to 90% of normal levels, PSD thickness increases by 20%-30%, and simultaneously recorded postsynaptic potential amplitudes are significantly enhanced, confirming improved synaptic function.

IV. Model Validation and Dose-Effect Relationships

In mouse models of aggressive behavior (e.g., isolation-induced aggression models, resident-intruder models), the neuroprotective effects of L-valine derivatives show clear dose dependence:

At low doses (20-50 mg/kg), they primarily regulate neurotransmitters (e.g., 5-HT, GABA) to exert short-term behavioral improvements, reducing attack frequency but with a tendency to rebound after discontinuation.

At moderate to high doses (100-200 mg/kg), they simultaneously activate anti-inflammatory, antioxidant, and neurotrophic pathways, achieving long-term neuroprotection. Improved aggressive behavior in model mice persists for 4-6 weeks post-discontinuation, with neuronal morphology and functional indices in the prefrontal cortex, hippocampus, and other regions approaching those of normal mice.

Additionally, different derivatives vary in duration of action: Ester derivatives, with high lipid solubility, achieve 30%-40% blood-brain barrier penetration and rapid onset (30-60 minutes); peptide derivatives (e.g., valine-glycine dipeptide) exhibit stable metabolism and longer duration (24-48 hours) but require higher doses to compensate for blood-brain barrier limitations.

L-valine derivatives intervene in the neuropathological processes of mouse aggressive behavior models through multi-target, multi-pathway mechanisms: They rapidly improve abnormal behavior by regulating neurotransmitters such as 5-HT and GABA, while achieving long-term protection of neuronal structure and function by inhibiting neuroinflammation, oxidative stress, and promoting neurotrophic factor expression. These findings provide experimental evidence for understanding the neuromodulatory mechanisms of branched-chain amino acid derivatives and offer potential directions for developing therapeutic drugs for aggression-related neuropsychiatric disorders (e.g., impulse control disorder, intermittent explosive disorder). Future research should further explore derivative structure-activity relationships and CNS-targeted delivery technologies to enhance specificity and safety.