Table 1 A comprehensive overview of the different classes of drugs that could be utilized to target the upregulation of synaptic communication and neuronal hyperexcitability in brain cancers, along with their mechanism of action and reported therapeutic implications

Anti-epilepsy drugs (AEDs)

- Levetiracetam (Keppra)

- Valproic acid (Depakote)

- Gabapentin (Neurontin)

- Phenytoin (Dilantin)

Impairs neuronal hyperexcitability,

downregulates voltage gated calcium channels (VGCC) and synaptogenesis

Levetiracetam use was associated with prolonged survival in patients with GBM treated with concurrent TMZ chemoradiotherapy [80].

Valproic acid and Gabapentin have been reported to improve outcomes in GBM patients [81, 82].

Gap-junction inhibitors

- Tonabersat

- Quinine

- Anandamide

- Mefloquine

- Oleamide

- Carbenoxolone

Impedes the electrical synaptic transmission between glioma and neuronal networks

Tonabersat was found to be an effective adjuvant treatment for GBM in mice models [83].

Mefloquine has been demonstrated to inhibit GBM angiogenesis and growth [84], while oleamide induces cell death in GBM RG2 cells [85].

Synaptogenesis inhibitors

- INCB7839 (ADAM10/17 inhibitor)

- LSKL (TSP-1 inhibitor)

- ZW251 (Glypican-3 targeting antibody drug conjugate)

- Pregabalin

Impair cancer growth by blocking synapse formation.

NCT04295759 is an ongoing clinical trial to test the efficacy of INCB7839 in inhibiting neuron-glioma interactions in pediatric glioma patients.

Silencing thrombospondin-1 has been reported to inhibit GBM invasion and growth [86].

Pregabalin was found to be effective in primary brain tumor patients [87].

AMPAR inhibitors

- Fycompa (Perampanel)

- Becampanel

- Fanapanel

- Tezampanel

Impede tumorigenesis by downregulating AMPAR.

Perampanel has been demonstrated to have anti-proliferative effects on GBM cells [88]. A currently ongoing phase IIa clinical trial, PerSurge (NOA-30), aims to evaluate the efficacy of Perampanel on GBM patients [89]. EU-CT registration number: 2023-503938-52-00 30.11.2023

NMDAR inhibitors

- Memantine

- Amantadine

- Ketamine

- Dizocilpine

- Ifenprodil

Impair NMDAR and downstream calcium signaling pathways in cancer cells, which promote glioma progression and metastasis.

Ketamine has been shown to suppress the proliferation of rat glioma cells [90] and inhibit the migration of glioma cells [91].

Blocking NMDAR signaling with Memantine or Ifenprodil suppressed the survival and migration of GBM cells [35].

GABA receptor antagonists

- Flumazenil

- Gabazine

- THIP

- TPMPA

- Levetiracetam

GABA-A receptor agonists

- QHii066

- KRM-II-08

- Moxidectin

Inhibit GABAergic synaptic transmission to suppress brain cancers.

GABA-A receptor agonists have shown efficacy in medulloblastoma, inducing HOXA5, upregulating p53, and promoting mitochondrial membrane depolarization through chloride-anion efflux.

Levetiracetam was found to suppress GABAergic neuron-to-glioma synaptic transmission, reduced glioma proliferation and improved the survival of mice injected with Diffuse midline glioma (DMG) xenografts [30].

QHii066 and KRM-II-08 have been shown to promote medulloblastoma cell apoptosis by inducing mitochondrial membrane depolarization and cell cycle arrest, while Moxidectin inhibited pediatric medulloblastoma progression by suppressing the PKA-Gli1 signaling axis [95, 98].