Neuropeptide Modulation in Epilepsy Management

Epilepsy is characterised by recurrent unprovoked seizures arising from aberrant neuronal excitability and synchronisation. Conventional antiepileptic drugs target ion channels and neurotransmitter systems but fail in about one third of patients. Neuropeptides offer a complementary strategy by modulating synaptic and network function through G protein–coupled receptors. Endogenous peptides such as neuropeptide Y and dynorphin are actively released during heightened neuronal activity, engaging presynaptic and postsynaptic pathways to dampen excitability. Advances in gene and cell therapies have enabled focal overexpression of neuropeptides or their receptors in seizure-generating regions, thereby achieving long-term homeostatic regulation. Preclinical studies have explored lentiviral or adeno-associated viral vectors to deliver peptide transgenes selectively to excitatory neurons, whilst chemogenetic approaches harness designer receptors to evoke peptide release on demand. Together, these strategies hold promise for the management of pharmacoresistant focal epilepsies, offering targeted modulation of pathological networks with minimal off-target effects. Beyond animal models, ex vivo experiments on human hippocampal tissue have demonstrated the translational potential of peptide-based interventions and support the development of next-generation therapies.

Research from Nature Portfolio

Work using human hippocampal slices from patients with drug-resistant temporal lobe epilepsy has provided direct evidence that exogenous application of neuropeptide Y markedly suppresses epileptiform discharges. In these experiments, tissue maintained in vitro displayed reduced frequency and amplitude of paroxysmal depolarising shifts when exposed to neuropeptide Y, an effect abolished by selective antagonism of the Y2 receptor. This proof-of-concept finding underscores the therapeutic viability of targeting endogenous anticonvulsant peptides in human brain tissue and lays the groundwork for clinical translation of peptide-based gene therapies.

Neuropeptide Modulation in Epilepsy Management publication trend

The graph below shows the total number of articles in neuropeptide modulation in epilepsy management across all publications each year (not limited to Nature Index journals).

Technical terms

Neuropeptide Y (NPY): An endogenous 36-amino-acid peptide that inhibits neuronal excitability via G protein–coupled receptors.

Y2 receptor: A presynaptic G protein–coupled receptor subtype that mediates the inhibitory actions of neuropeptide Y.

Dynorphin: An endogenous opioid peptide released during high-frequency stimulation to modulate synaptic transmission and network excitability.

Adeno-associated viral vector (AAV): A gene delivery vehicle commonly used for stable transgene expression in neuronal populations with low immunogenicity.

References

1. Gene therapy for epilepsy targeting neuropeptide Y and its Y2 receptor to dentate gyrus granule cells. EMBO Reports (2024).
2. Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy. EMBO Molecular Medicine (2019).
3. Disease Modification by Combinatorial Single Vector Gene Therapy: A Preclinical Translational Study in Epilepsy. Molecular Therapy — Methods & Clinical Development (2019).
4. Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients. Scientific Reports (2019).