Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.

Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons.

In the adult mouse hippocampus, NMDA receptors (NMDARs) of CA1 neurons play an important role in the synaptic plasticity. The location of NMDARs can determine their roles in the induction of long-term potentiation (LTP). However, the extrasynaptic NMDARs (ES-NMDARs) dependent LTP haven't been reported. Here, through the use of a 5-Hz stimulation and MK-801 (an irreversible antagonist of NMDARs) in the CA1 neurons of adult mice hippocampal slices, synaptic NMDARs were selectively inhibited and NMDAR-mediated excitatory postsynaptic currents were not recovered. We found that a robust LTP was induced by 3-train 100-Hz stimulation when the synaptic NMDARs and extrasynaptic NR2B containing NMDARs were blocked, but not in the any of the following conditions: blocking of all NMDARs (synaptic and extrasynaptic), blocking of the synaptic NMDARs, and blocking of the synaptic NMDARs and extrasynaptic NR2A-containing NMDARs. The results indicate that this LTP is ES-NMDARs dependent, and NR2B-containing ES-NMDARs modulates the threshold of LTP induction.

[Effect of acute stress stimulation on the seizure induction in epileptic model rats].

This study was undertaken to observe the effect of acute stress on seizure occurrence in chronic period of epileptic model rats. Lithium-pilocarpine (LiCl-PILO)-induced epileptic rat model was constructed. At the spontaneous recurrent seizure period, acute stress stimulations such as cat's urine and foot electrical shock were applied to observe the behavioral changes and seizure occurrence. The results showed that after the cat's urine stimulation, the self-directed behaviors of the epileptic model rats decreased significantly, while the risk assessment behaviors increased significantly. The seizure occurrence, however, was not observed during the 45 min after the stimulation. Applying electrical foot shocks also did not evoke seizures in epileptic model rats. On the contrast, intra-peritoneal injection of low dose of pentylenetetrazole (PTZ, 30 mg/kg) evoked seizure more efficiently, and the duration of seizure activity was extensively prolonged in epileptic model rats than that of control rats. Taken together, these results indicate that although applying stress stimulations such as cat's urine and electrical foot shock cause several behavioral changes, they are not severe enough to evoke seizure in epileptic model rats.

Functional roles of synaptic and extrasynaptic NMDA receptors in physiological and pathological neuronal activities.

The N-methyl-D-aspartate (NMDA) receptor is a major type of ionotropic glutamate receptor. Many studies have shown that NMDA receptors play a pivotal role in the central nervous system (CNS) under both physiological and pathological conditions. The functional diversity of NMDA receptors can be mainly attributed to their different subunit compositions that perform multiple functions in various situations. Furthermore, recent reports have indicated that synaptic and extrasynaptic NMDA receptors have distinct compositions and couple with different signaling pathways: while synaptic NMDA receptors tend to promote cell survival, extrasynaptic NMDA receptors promote cell death. Currently, intensive efforts are being made to study the pathological role of extrasynaptic NMDA receptors in order to find a more effective approach for the treatment of neurologic disorders. Here we reviewed some recent progress on the participation of synaptic and extrasynaptic NMDA receptors in neurologic diseases including epilepsy, ischemia, schizophrenia, depression and some neurodegenerative diseases.