*4.8. Neuroprotective Activity*

Supplementation with *M. koenigii* leaf extracts has been reported in the management of a wide spectrum of neurodegenerative diseases, like AD, PD, and others [30,33–35,41]. *M. koenigii* promotes neuroprotective potential against orofacial dyskinesia induced by resperine. Additionally, it stabilizes the levels of protective antioxidant enzymes like SOD, catalase (CAT), and GSH, and inhibits LPO in the forebrain regions of reserpine-treated animals. Furthermore, it has been shown to significantly inhibit reserpine-induced abnormalities in behavior. Similarly, treatment with *M. koenigii* significantly restored the levels of protective antioxidant enzymes (that is, SOD, CAT, and GSH) and inhibited LPO in the forebrain region when compared with reserpine, and it also inhibited catalepsy induced by haloperidol [36]. Isolongifolene (ILF), a tricyclic sesquiterpene of *M. koenigii*, has been reported to render neuroprotective effects against rotenone-induced mitochondrial dysfunction, oxidative stress, and apoptosis in a cellular model. Cytotoxicity, oxidative stress, and mitochondrial dysfunction were also attenuated by ILF in SH-SY5Y cells, which down-regulated Bax and caspases-3, -6, -8, and -9 expression, and up-regulated Bcl-2 expression. IFL was proved to regulate p-P13K, p-AKT, and p-GSK-3 beta expressions [87]. Preclinical studies have reported that *M. koenigii* leaves could enhance memory in rats [119]. The possible neuroprotective potential of amethanolic extract of *M. koenigii* leaves was exhibited in a two-vessel occlusion (2VO) rat model of partial global cerebral ischaemia. The Morris water maze test was implemented to assess the rats' cognitive function postoperatively. Brain samples were histopathologically examined for viable neurons within the CA1 hippocampal region. Test findings showed that *M. koenigii* leaves positively improved memory and learning impairments. *M. koenigii* leaf extracts modestly improved memory in rats with chronic partial global cerebral ischemia [120]. The various activities of *M. koenigii* against neurotoxicity are shown in Figure 3.

**Figure 3.** Neuroprotective effect in in vitro and in vivo studies produced by bioactive compounds from *M. koenigii.* PI3: phosphatidylinositol 3 kinase; GSK3β: Glycogen synthase kinase 3 beta; Ach: Acetylcholine; Bax: Bcl2-Associated X protein.
