AD is the most prominent dementia in senile population affecting approximately 5% of the over 65-year old populations, but the cause of AD remains largely unknown. In the pathogenesis of AD, the inflammation mechanism is seemed to play an important role . The senile plaque is the hallmark of AD. The core of the senile plaque is the deposition of β-amyloid (Aβ) and the activated microglia and astroglia are around the senile plaque. In these glias, numerous inflammation factors including IL-1β, interleukin -6(IL-6), tumor necrosis factor-α (TNF-α) and iNOS etc, are overexpressed. These inflammation factors have been seemed to be neurotoxic. At the same time, some epidemiological studies demonstrated that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) could prominently delay the onset of AD [2–5]. The current drugs for AD treatment including cholinesterase inhibitors (donepezil, rivastigmine and galanthamin) and N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) which were approved by Food and Drug Administration of USA (FDA) are symptomatic treatment, but these drugs usually can not delay the development of AD. Anti-inflammation drugs are expected to delay AD, but most clinical research results of NSAIDs on AD are negative . Moreover some selective COX-2 inhibitors increased the occurrence of cardiovascular accidents [7, 8].
Berberine is an isoquinoline alkaloid with a long history of medicinal usage in China. It exists in Hydrastis canadensis (goldenseal), Cortex phellodendri (Huangbai) and Rhizoma coptidis (Huanglian). These medicinal plants have been widely used as traditional medicines for treating diarrhea and gastrointestinal disorders for a long time in China. Berberine, the major ingredient of these herbs, has multiple pharmacological effects. It is a acetylcholinesterase inhibitor similar to Galanthamine, a drug treating AD, and might be a low-molecular-weight neurotrophic drug to neurodegeneration disorder such as AD by potentiating the nerve growth factor (NGF)-induced differentiation in neural cells ; berberine is a novel cholesterol-lowering drug distinctly from statins by stabilizating the low density lipoprotein receptor (LDLR) mRNA to increase LDLR expression and inhibiting lipid synthesis[11, 12]. Berberine is also able to exert a glucose-lowering effect by insulin independent manner , stimulating insulin secretion and effectively sensitizing insulin activity [14, 15]. So berberine can play an important role on metabolic syndrome. Berberine could improve quality of life and decrease ventricular premature complexes and mortality in patients with chronic congestive heart failure . Berberine has potential in the prevention of atherosclerosis and restenosis [17, 18]. Berberine can block transient outward potassium current (IA) and delayed rectifier potassium current (IK) in a concentration-dependent manner in acutely isolated CA1 pyramidal neurons of rat hippocampus . A recent study demonstrated that mutations in voltage-gated potassium channel KCNC3 caused adult-onset ataxia , and potassium channels are regarded to play a key role in neurodegeneration including AD . So berberine might be useful for the treatment of neurodegeneration disorders including AD.
Except the above pharmacological effects, extracts obtained from the roots of berberidaceae species have been used in Eastern and Bulgarian folk medicines for the treatment of rheumatic and other chronic inflammatory disorders. Berberine suppressed a delayed type hypersensitivity (DTH) reaction in a chronic inflammatory model of adjuvant arthritis and diminished the antibody response against sensitization red blood cell (SRBC) in vitro . In recent years, it was demonstrated that berberine could inhibit the expression of some inflammation factors. It might inhibit arachidonic acid metabolism in rabbit platelets and endothelial cells . Berberine could decrease cyclooxygenase-2 (COX-2) expression by directly inhibiting the activator protein-1(AP-1) binding and IL-1β and TNF-α productions in HepG2 cells and cardiomyocyte through nuclear factor-κB (NF-κB) signaling pathway [24–27]. It could decrease IL-6 production in esophageal cancer cells and inhibit expression of iNOS mRNA in ethanol-induced gastric ulcer mice [28, 29].
So berberine might be a very promising drug to treat the cardiac disease, stroke, diabetes and hyperlipoidemia and chronic inflammation diseases. So far, whether berberine might be beneficial to AD by decreasing the inflammation factors expression has not been studied. To test the hypothesis that berberine might inhibit the inflammation factors IL-1β and iNOS expression in the rat model of AD, we used the rat model of AD established by injecting Aβ(1–40)(5 μg) into the bilateral hippocampuses with stereotaxic coordinates and gave the rats berberine chloride (50 mg/kg) intragastricly for 14 days. It was very surprising that we found berberine chloride could significantly ameliorate the spatial memory impairment and increase these two factors expression.