Mahanimbine improves cholinergic transmission in lipopolysaccharide-induced neuroinflammation model.

Inflammatory processes within the brain represent a potential pathogenic factor in several neurodegenerative conditions. The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory responses. Studies indicated that acetylcholine attenuates the production of TNF-alpha, IL-1beta, IL-6 and IL-18 by macrophages at the post-transcriptional stage. Current literature had demonstrated the role of various alkaloids in neuroprotection. Mahanimbine is a major bioactive carbazole alkaloid derived from Murraya koenigii leaves (1). Thus, we aimed to investigate the potential role of mahanimbine on cholinergic transmission in lipopolysaccharide (LPS)-induced neuroinflammation model. Three-month aged male ICR mice were administered mahanimbine (1, 2 and 5mg/kg) orally for thirty consecutive days. The control and LPS-treated groups were treated with the vehicle (0.5% w/v CMC) for the same duration of time. Excluding the control group, all animals were given an intra-peritoneal injection of LPS (250μg/kg) daily for last 4 days of the treatment for inflammation induction (2). At the end of the treatment, brain tissues were collected to measure cyclooxygenase (COX), acetylcholine and acetylcholinesterase levels. The data were analysed using one-way ANOVA followed by Tukey-Kramer multiple comparison test. The significant elevation of COX activity in the LPS-treated group has confirmed the formation of neuroinflammation in mouse brain. It must be noted that the activity of COX was significantly attenuated (P<0.001) by administration of all the doses of mahanimbine as compared to LPS group. Meanwhile, the validation of COX activity had been confirmed using gene expression with RT-PCR to observe the expression of COX-2 genes. Furthermore, mahanimbine under the doses of 1, 2 and 5mg/kg, significantly increased the level of ACh (P<0.01, P<0.05, P<0.05; respectively) and decreased the level of AChE in brain homogenate (P<0.001, P<0.01, NS; respectively) as compared with LPS-induced group (Fig. 1).

Fig. 1 Mean ± SEM (n=6) of the effect of mahanimbine on neuroinflammation and cholinergic activities in LPS-induced model (*P< 0.05,**P< 0.01, ***P<0.001 vs control group; #P< 0.05 ##P< 0.01 ### P< 0.001 vs LPS group)

The inhibition of total COX activity and expression of COX-2 genes with mahanimbine treatment confirmed its anti-inflammatory ability. Additionally, mahanimbine facilitated the central cholinergic activity by elevating the acetylcholine level and inhibiting the acetylcholinesterase enzyme activity in the brain. The above results suggested that mahanimbine may be a useful agent for the prevention of neuroinflammation associated with development or progression of neurodegeneration.

(1) Dineshkumar et al. (2010). Int J Phytomed 2: 22-30.

(2) Anaeigoudari et al. (2015). Arq Neuropsiquiatr 73(9): 784-90.