Vascular dementia develops when impaired blood supply damages the brain, affecting memory, attention, and executive function. Its complex pathology includes neuronal injury, inflammation, and disturbances in communication between brain regions. Huperzine A inhibits acetylcholinesterase, the enzyme that breaks down acetylcholine, and its cognitive effects have traditionally been attributed to increased availability of this neurotransmitter. However, reported neuroprotective and anti-inflammatory effects suggest that this explanation is incomplete. Researchers still need to understand how acetylcholine changes translate into protection of individual neurons and improvements across cognitive networks. Identifying these connections could reveal targets for approaches that address several interacting disease processes.
A study (DOI: 10.48130/targetome-0026-0042) published in Targetome on 10 September 2026 by Haiping Hao's & Xiao Zheng's team, China Pharmaceutical University, reports that acetylcholine signaling in the dorsal striatum links receptor-mediated neuronal protection with modulation of a striatum–substantia nigra circuit to improve cognitive performance.
The researchers combined behavioral testing, brain tissue analysis, neurotransmitter profiling, cultured-neuron experiments, calcium imaging, viral tracing, and chemogenetic manipulation to investigate huperzine A’s effects. They established a mouse model using bilateral common carotid artery occlusion and assessed cognition with the Morris water maze, novel object recognition, and Y-maze tests. Huperzine A improved performance across these tasks without significantly changing locomotor activity. Tissue staining showed reduced neuronal damage and microglial overactivation, alongside restoration of dendritic spine density and neuronal branching. Liquid chromatography–mass spectrometry measurements revealed increased acetylcholine concentrations in several brain regions, including the striatum. Delivering huperzine A, acetylcholine, or the acetylcholinesterase inhibitor donepezil directly into the dorsal striatum reproduced cognitive improvements, supporting this region’s role in the response. Receptor-blocking experiments then distinguished the signaling involved: blocking nicotinic receptors weakened huperzine A’s benefits, whereas blocking muscarinic receptors did not produce comparable effects. More specifically, an α7 nicotinic receptor antagonist compromised cognitive improvements in mice. In primary striatal neurons subjected to oxygen–glucose deprivation followed by reoxygenation, acetylcholine promoted neurite growth, and the same antagonist prevented this response. Huperzine A alone did not significantly enhance neurite growth in that experiment, supporting an indirect action through acetylcholine. Fiber photometry and two-photon imaging showed that huperzine A increased calcium activity in striatal GABAergic neurons. Viral tracing and activity mapping helped identify downstream connections, which the researchers tested using chemogenetics to selectively alter neuronal activity. These experiments implicated the connection between dorsal striatal and substantia nigra pars reticulata GABAergic neurons. Crucially, activating GABAergic neurons in the substantia nigra during huperzine A treatment substantially weakened its cognitive benefits, bringing behavioral performance back toward untreated model levels. Together, the results support a dual mechanism in which local acetylcholine signaling contributes to neuronal protection and circuit regulation, although how these effects interact over time remains to be established in further experiments.
The study expands understanding of huperzine A beyond its established role in preventing acetylcholine breakdown. It highlights the dorsal striatum as a site where neurotransmitter regulation may connect cellular protection with cognitive network function. These preclinical findings support further investigation of coordinated therapeutic targets, while additional studies are needed to clarify receptor specificity, interactions between the two mechanisms, and relevance to human vascular dementia.
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References
DOI
10.48130/targetome-0026-0042
Original Source URL
https://doi.org/10.48130/targetome-0026-0042
Funding information
This work was supported by the National Key Research and Development Program of China (2024YFA1308200 to Zheng X), the National Natural Science Foundation of China (82321005 to Hao H), and the Natural Science Foundation of Jiangsu Province (BK20240095 to Zheng X).
About Targetome
Targetome refers to the complete collection of molecular targets (e.g., proteins, RNA or DNA) that interact with and mediate the effect of a specific biomolecule, such as a drug, toxin, metabolites, transcription factor or microRNA, within a biological system. Targetome (Print ISSN 3071-0596; e-ISSN 3070-3808) is an open access journal publishing rigorously peer-reviewed original research articles, reviews, break-through methods, and perspectives that advance our understanding, identification and validation of molecular targets for new drug development.