Trans-Anethole Alleviates Trimethyltin Chloride-Induced Impairments in Long-Term Potentiation.

Trans-anethole is an aromatic compound that has been studied for its anti-inflammation, anticonvulsant, antinociceptive, and anticancer effects. A recent report found that trans-anethole exerted neuroprotective effects on the brain via multiple pathways. Since noxious stimuli may both induce neuronal cell injury and affect synaptic functions (e.g., synaptic transmission or plasticity), it is important to understand whether the neuroprotective effect of trans-anethole extends to synaptic plasticity. Here, the effects of trimethyltin (TMT), which is a neurotoxic organotin compound, was investigated using the field recording method on hippocampal slice of mice. The influence of trans-anethole on long-term potentiation (LTP) was also studied for both NMDA receptor-dependent and NMDA receptor-independent cases. The action of trans-anethole on TMT-induced LTP impairment was examined, too. These results revealed that trans-anethole enhances NMDA receptor-dependent and -independent LTP and alleviates TMT-induced LTP impairment. These results suggest that trans-anethole modulates hippocampal LTP induction, prompting us to speculate that it may be helpful for improving cognitive impairment arising from neurodegenerative diseases, including Alzheimer's disease.

Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.

We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C ßII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.

Neuregulin-1 prevents amyloid ß-induced impairment of long-term potentiation in hippocampal slices via ErbB4.

Neuregulin-1 (NRG1) participates in numerous neurodevelopmental processes and plasticity of the brain. Despite this, little is known about its role in Alzheimer's disease (AD). Amyloid ß (Aß) peptide is generally believed to play a critical role in the pathogenesis of AD. The present study examined the effect of synthetic Aß1₋42 peptides on long-term potentiation (LTP) in the CA1 region of mice hippocampal slices, a cellular model of learning and memory. We found that application of a test dose of Aß1₋42 (200 nM) significantly inhibited the development of LTP without affecting basal synaptic transmission. Pretreatment with NRG1 effectively prevented Aß1₋42-induced impairment of LTP, an effect that was dose-dependent. This LTP-restoring action of NRG1 was almost completely abolished by blocking ErbB4, a key NRG1 receptor, suggesting that NRG1 acts through ErbB4 to exert its protective action on LTP. The present study thus provides the first demonstration that NRG1/ErbB4 protects against Aß-induced hippocampal LTP impairment, suggesting that NRG1 may be a promising candidate for the treatment of early-stage AD.