Oleamide was first known as a sleep-inducing fatty acid amide, and later shown to have wide range of neuropharmacological effects upon different neurochemical systems. However, the effects of oleamide on brain damage have scarcely been studied, and the molecular mechanisms and sites of its action remain elusive. Kainic acid (KA) has been used to produce an epileptic animal model that mimics human temporal lobe epilepsy and to induce calpain-activated excitotoxicity, which occurs in numerous neurodegenerative disorders. In this study, we examined whether oleamide protects against the KA-induced excitotoxic brain damage accompanied by behavioral seizure activity and neuronal cell death. Moreover, whether these effects of oleamide were mediated by calpain activity-related cellular mechanisms was investigated. KA-induced epileptic rats were produced by an intrastriatal injection of KA (5 nmole). Oral administration of oleamide (0.5, 2, and 10 mg/kg) 30 min prior to the KA injection showed dose-dependent inhibition of the KA-induced behavioral seizure activities that were monitored starting from 60 to 180 min post-surgery. Further repetitive oral administration of oleamide (once per day) for the next 4 consecutive days post-KA injection produced significant neuroprotection against the disrupted neuronal integrity that resulted from KA-induced excitotoxic damage that was also demonstrated by staining of striatal tissue sections with cresyl violet, hematoxylin/eosin, and fluoro-Jade B. In addition, oleamide blocked the KA-induced cleavage of cyclin-dependent kinase-5 coactivator (Cdk5-p35) and collapsin response mediator protein-2, which are believed to be mediated by calpain activation in striatal tissues dissected from KA-induced epileptic rats. Oleamide also reversed the KA-induced reduction in expression of an endogenous calpain inhibitory protein, calpastatin, and a marker of synaptic activity, synapsin-II. The hypothesis that oleamide could induce direct calpain inhibition was further investigated using in vitro calpain assays in both brain tissue and a cell-free and calpain-overexpressed neuronal cell system. These findings together suggest that oleamide has protective effects against excitotoxicity-induced neuronal death and behavioral seizure, partly via its direct calpain inhibitory activity.

Collapsin response mediator protein (CRMP)-2 and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are associated with common physiological functions such as neuronal polarity, axonal outgrowth, and synaptic strength, as well as various brain disorders including epilepsy. But, their regulatory and functional links are unclear. Alterations in CRMP-2 expression that lead to its functional changes are implicated in brain disorders such as epilepsy. Here, we investigate whether changes in CRMP-2 expression, possibly regulated by mTOR-related signaling, correlates with neuronal growth and viability. Inhibition of mTOR and/or phosphoinositol-3-kinase (PI3K) led to deceased p-S6K, and p-S6 signals also reduced CRMP-2 expression. These changes corresponded to inhibition of neuronal viability and proliferation in cultured hippocampal HT-22 cells under both basal serum-free and serum- or insulin-induced mTOR pathway-activated conditions. CRMP-2 expression tended to be increased by mTOR activation, indicated by an increase in p-S6/S6 level, in pentylentetrazole-induced epileptic rat hippocampal tissues was also significantly reduced by mTOR inhibition. Knockdown of CRMP-2 by si-RNA reduced the neuronal viability without changes in mTOR signaling, and overexpression of CRMP-2 recovered the glutamate-induced neurotoxicity and decrease of mTOR signaling in HT-22 cells. In conclusion, CRMP-2 protein expression controlled by the PI3K-mTOR-S6K signaling axis exerts its important functional roles in neuronal growth and survival.

The translationally controlled tumor protein (TCTP), initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF). TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of TCTP in the neurotransmitter release from a neurosecretory, pheochromocytoma (PC12) cells. Treatment with recombinant TCTP (rTCTP) enhanced both basal and depolarization (50 mM KCl)-evoked [³H]dopamine release in concentration- and time-dependent manners. Interestingly, even though rTCTP induced the increase in intracellular calcium levels ([Ca²⁺]_i), the rTCTP-driven effect on dopamine release was mediated by a Ca²⁺-independent pathway, as evidenced by the fact that Ca²⁺-modulating agents such as Ca²⁺ chelators and a voltage-gated L-type Ca²⁺-channel blocker did not produce any changes in rTCTP-evoked dopamine release. In a study to investigate the involvement of phospholipase A₂ (PLA₂) in rTCTP-induced dopamine release, the inhibitor for Ca²⁺-independent PLA₂ (iPLA₂) produced a significant inhibitory effect on rTCTP-induced dopamine release, whereas this release was not significantly inhibited by Ca²⁺-dependent cytosolic PLA₂ (cPLA₂) and secretory PLA₂ (sPLA₂) inhibitors. We found that rTCTP-induced dopamine release from neuronal PC12 cells was modulated by a Ca²⁺-independent mechanism that involved PLA₂ in the process, suggesting the regulatory role of TCTP in the neuronal functions.

Background: Pharmaceutical interventions play a key role in the care of older people experiencing polypharmacy. Despite the rapid increase in the aging population in Asia, there is a lack of evidence regarding the effectiveness of pharmacist interventions on older adult’s healthcare. This systematic review and meta-analysis assessed the effects of pharmacist interventions in Asian health care environments on hospitalization, mortality, and quality of life (QoL) among older people in Asia. Methods: A comprehensive search was conducted across 5 databases, encompassing studies published from inception through June 2023. Only studies involving pharmacist interventions for people aged 65 years or older, residing in Asian countries, were considered. Studies without evidence of pharmacist involvement or conducted outside of Asia were excluded. Data extraction was performed by two reviewers, one reviewer (I.K.) performed the initial extraction, and another reviewer (G.R.) verified the extracted data. Forest plots were generated using a random effects model to obtain risk ratios or pooled standardized mean differences (SMDs). Results: A total of 170 articles underwent thorough review, and ultimately, ten studies meeting the inclusion criteria were included in the meta-analyses. These studies encompassed diverse healthcare settings such as outpatient, inpatient, and nursing homes, with sample sizes ranging from 32 to 306 older people. Pharmacist interventions were found to significantly reduce hospitalization rates (n = 5, risk ratio = 0.57, 95% CI = 0.41–0.81) and mortality rates (n = 4, risk ratio = 0.57, 95% CI = 0.37–0.88) among older people. The analysis revealed less significant improvement in QoL in these patients than in those receiving usual care (n = 6, SMD = 0.36, P = 0.057). Conclusions: These findings highlight the crucial role of pharmacists within healthcare teams in Asian countries. Pharmacist interventions have an impact on reducing hospitalization and mortality rates among the elderly people, underscoring the importance of optimizing patient outcomes in Asia.