Cognitive impairments induced by severe acute pancreatitis are attenuated by berberine treatment in rats

Abstract

Cognitive impairments induced by severe acute pancreatitis (SAP) are severe complications, for which there are a lack of effective pharmacological treatment strategies. Berberine is an isoquinoline alkaloid extracted from the Chinese herb, Coptis rhizome, which exhibits numerous biological effects on gastrointestinal disorders. However, the effects of berberine on SAP‑induced cognitive impairments remain unknown. The present study aimed to investigate the effects of berberine on cognitive impairments associated with SAP. Wistar rats were randomly divided into Sham, Sham + berberine, SAP and SAP + berberine groups. Rats were intraperitoneally injected with L‑arginine (3 g/kg) to induce SAP. Subsequently, selected rats were intragastrically administered berberine (100 mg/kg) once daily for 6 consecutive days. Disease severities of rats were investigated 48 h post‑induction of SAP via determination of serum amylase levels and hematoxylin and eosin staining. Survival rates, performance of behavioral tests (automated rotarod and fear conditioning tests), blood brain barrier (BBB) permeability, and the expression levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑1β in hippocampal tissues were also determined. Proteins associated with apoptosis and necroptosis in the hippocampal tissues of SAP rats, including caspase‑3, receptor‑interacting protein kinase (RIP)1 and RIP3, were detected via western blotting. The results revealed that treatment with L‑arginine induced SAP, which subsequently resulted in increased BBB permeability, mortality rates and cognitive deficits in rats. The expression levels of TNF‑α, IL‑1β, caspase‑3, RIP1 and RIP3 were significantly increased in the hippocampal tissues of SAP rats, thus suggesting that neuroinflammation, apoptosis and necroptosis may be involved in neurodegeneration associated with the development of SAP. Notably, administration of berberine protected the integrity of the BBB, decreased levels of brain inflammation and mortality rates, and attenuated increased levels of proteins associated with apoptosis and necroptosis and cognitive deficits associated with SAP in rats. The results of the present study demonstrated that daily treatment with berberine may attenuate cognitive deficits and reduce associated mortality via exhibition of anti‑neuroinflammatory effects and attenuation of neuronal apoptosis and necroptosis in the hippocampal tissues of SAP rats.

NMDA receptor‐dependent and ‐independent effects of natural compounds and crude drugs on synaptic states as revealed by drebrin imaging analysis

“…Berberine, a common extract found in these two drugs, has anti‐apoptotic properties, anti‐neuroinflammatory effects, and mitoprotective effects (Kalalian‐Moghaddam et al., 2013; Ou et al., 2018; Zhao et al., 2019). CR has been shown to contain more berberine than PB (Anetai, 1994; Anetai et al., 1987), which may result in a stronger effect on the reduction in drebrin cluster densities for CR compared with PB.…”

“…Nobiletin, a citrus flavonoid, diosgenin, a well‐known steroidal sapogenin from wild yam, and tenuifolin, a bio‐active terpenoid from Polygala tenuifolia , have been well‐studied, especially in relation to AD (Liu et al., 2015; Lv et al., 2009; Matsuzaki et al., 2006; Nakajima & Ohizumi, 2019; Onozuka et al., 2008; Tohda et al., 2012; Wang, Jin, et al., 2019; Youn et al., 2019). Uncaria Hook (UH), Bezoar Bovis (BB), Coptis Rhizome (CR), Phellodendron Bark (PB) and Polygala Root (PR) are also well‐known for their effects on cognitive dysfunction and AD (Cai et al., 2013; Hu et al., 2014; Kalalian‐Moghaddam et al., 2013; Kanno et al., 2013; Ou et al., 2018; Park et al., 2002; Zhao et al., 2016, 2019). CR, PB and PR have previously been examined in clinical studies (Linn et al., 2012; Shin et al., 2009).…”

Selective Inhibition of Soluble TNF Using Xpro1595 Relieves Pain and Attenuates Cerulein-induced Pancreatic Pathology in Mice, With a Possible Link to Central Pain Processing

“…Specifically, rodent models show hippocampal TNF/TNFR1 activity regulates hindpaw neuropathic pain (52,58). Since acute pancreatitis promotes a systemic inflammatory response in both humans and rodents (69,70), including TNF upregulation within the hippocampus (71), we sought to determine whether our model of pancreatitis promotes an inflammatory state within the hippocampus that could play a role in the development of peripheral hindpaw mechanical hypersensitivity.…”

Murine Models of Acute Pancreatitis: A Critical Appraisal of Clinical Relevance

“…Mizunuma et al [103] proposed a model that established the intraperitoneal route with L-arginine hydrochloride. Several modifications of this model showed that higher doses can produce high mortality, repeated doses promote necrosis, and reduced doses may delay the time of onset of AP [73,74,104]. Table 3 summarizes the most commonly used doses of L-arginine when administered by the intraperitoneal route.…”