https://orcid.org/0000-0001-5587-6067
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ABSTRACT
Introduction
Epilepsy is a chronic neurological condition characterized by a persistent propensity for seizure generation. About one-third of patients do not achieve seizure control with the first-line treatment options, which include >20 antiseizure medications. It is therefore imperative that new medications with novel targets and mechanisms of action are developed.
Areas covered
Clinical studies and preclinical research increasingly implicate Non-receptor tyrosine kinases (nRTKs) in the pathogenesis of epilepsy. To date, several nRTK members have been linked to processes relevant to the development of epilepsy. Therefore, in this review, we provide insight into the molecular mechanisms by which the various nRTK subfamilies can contribute to the pathogenesis of epilepsy. We further highlight the prospective use of specific nRTK inhibitors in the treatment of epilepsy deriving evidence from existing literature providing a rationale for their use as therapeutic targets.
Expert opinion
Specific small-molecule inhibitors of NRTKs can be employed for the targeted therapy as already seen in other diseases by examining the precise molecular pathways regulated by them contributing to the development of epilepsy. However, the evidence supporting NRTKs as therapeutic targets are limiting in nature thus, necessitating more research to fully comprehend their function in the development and propagation of seizures.
Article highlights
Non-receptor protein tyrosine kinases (NRTKs) regulate signaling pathways implicated in the development of epilepsy.
The molecular mechanisms regulated by the various NRTK subfamilies and their precise role in epilepsy are poorly understood.
Small molecule inhibitors of NRTKs can be utilized for targeted therapy in epilepsy.
Understanding the role of NRTKs in mediating the pathogenesis of epilepsy will help in deciphering the molecular mechanisms leading to the disease and developing novel therapeutic targets.
Abbreviations
| Abbreviations | = | Full Form |
| Abl | = | Abelson kinase |
| Acks | = | Activated Cdc42 Kinase |
| ASMs | = | Anti-seizure medications |
| BBB | = | Blood brain barrier |
| CADTK | = | Calcium-dependent-protein tyrosine kinase |
| CAKβ | = | Cell adhesion kinase-β |
| CDK5 | = | Cyclin-dependent kinase 5 |
| DRE | = | Drug-resistant epilepsy |
| EEG | = | Electroencephalography |
| EGF | = | Epidermal growth factor |
| FAK | = | Focal adhesion kinase |
| FAT | = | Focal-adhesion targeting domain |
| FERM | = | Four-point-one, ezrin, radixin, moesin domain |
| GABA | = | Gamma-aminobutyric acid |
| GPCR | = | G protein couple receptor |
| GSK3β | = | Glycogen synthase kinase-3 beta |
| Ig | = | Immunoglobulin |
| JAK | = | Janus kinase |
| JH2 | = | Janus homology domain 2 |
| KDa | = | Kilo dalton |
| MEG | = | Magnetoencephalography |
| MRI | = | Magnetic resonance imaging |
| NMDAR | = | N-methyl-D-aspartate receptor |
| nRTKs | = | Non-receptor tyrosine kinases |
| PD | = | Parkinson disease |
| PH | = | Pleckstrin homology domain |
| PKC | = | Protein kinase C |
| PR | = | Proline rich region |
| PTKs | = | Protein tyrosine kinases |
| PTPN11 | = | Tyrosine-protein phosphatase non-receptor 11 |
| Pyk2 | = | Protein tyrosine kinase |
| RAFTK | = | Related adhesion focal tyrosine kinase |
| ROS | = | Reactive oxygen species |
| RTKs | = | Receptor tyrosine kinases |
| SE | = | Status Epilepticus |
| SH2 | = | Src homology 2 |
| SH3 | = | Src homology 3 |
| SOC | = | Suppressor of cytokine signaling |
| STAT | = | Signal transducer and activator of transcription |
| SYK | = | Spleen tyrosine kinase |
| TBI | = | Traumatic brain injury |
| TK | = | Tyrosine kinase |
| TLE | = | Temporal Lobe Epilepsy |
| VNS | = | Vagus nerve stimulation |
| μflow-MEA | = | Microfluidic-multiple electrode array |
Disclosure statement
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.