Phyto-Carbazole Alkaloids from the Rutaceae Family as Potential Protective Agents against Neurodegenerative Diseases

Abstract

Plant-derived (phyto) carbazole alkaloids are an important class of compounds, presented in the family of Rutaceae (Genera Murraya, Clausena, Glycosmis, Micromelum and Zanthoxylum). Due to several significant biological activities, such as antitumor, antibacterial, antiviral, antidiabetic, anti-HIV and neuroprotective activities of the parent skeleton (3-methylcarbazole), carbazole alkaloids are recognized as an important class of potential therapeutic agents. Neurodegenerative diseases (NDs) may exhibit a vast range of conditions, affecting neurons primarily and leading ultimately to the progressive losses of normal motor and cognitive functions. The main pathophysiological indicators of NDs comprise increasing atypical protein folding, oxidative stresses, mitochondrial dysfunctions, deranged neurotransmissions and neuronal losses. Phyto-carbazole alkaloids can be investigated for exerting multitarget approaches to ameliorating NDs. This review presents a comprehensive evaluation of the available scientific literature on the neuroprotective mechanisms of phyto-carbazole alkaloids from the Rutaceae family in ameliorating NDs.

Keywords: Alzheimer’s disease; Rutaceae; neurodegenerative disease; neuroinflammation; oxidative stress; phyto carbazole alkaloid.

Figure 1

Biogenetic pathway in the formation of carbazole and 3-methyl carbazole alkaloids and core structure of the diverse carbazole alkaloids isolated from nature.

Figure 2

Potential neuroprotective phyto-carbazole alkaloids from Murraya koenigii.

Figure 3

Potential neuroprotective phyto-carbazole alkaloids from the species of the genus Clausena.

Figure 4

Potential phyto-carbazole alkaloids from Glycomis pentaphylla.

Figure 5

Potential phyto-carbazole alkaloids from the species of the genus Micromelum.

Figure 6

Potential neuroprotective phyto-carbazole alkaloids from the species of the genus Zanthoxylum.

Figure 7

Multi-target mechanism displayed by Rutaceae family plant extracts and carbazole alkaloids in neurodegenerative diseases. Phyto extracts and carbazole alkaloids from Rutaceae family exerted a multi-target approach in ameliorating symptoms of AD. PP2A and BDNF activity/expression was decreased in AD, which stimulated the hyper-phosphorylation of Tau and APP, leading to overproduction of Aβ. Phyto-carbazoles prevented Aβ aggregation by inhibiting cleavage of the APP by BACE-I, as well as by upregulating the expression of PP2A and BDNF. This caused a shift in the non-amyloidogenic pathway and reduced the levels of produced Aβ. A number of phyto-carbazoles were shown to reduce the levels of pro-inflammatory cytokines and inflammatory mediators (IL-6, IL-1β, NF-kβ, TNF-α, iNOS, COX-2). Nrf2/HO-1 was an antioxidant signaling pathway, which was required for neuronal cell proliferation and survival. Down-regulation of this pathway was associated with various NDs. Phyto-carbazoles provided the neuroprotection by upregulating the expressions of the Nrf2/OH-1 pathway. They also reduced the oxidative stress by increasing the levels of antioxidant enzymes (SOD, CAT, GSH, GRD, GPx) and reducing lipid peroxidation (LPO). Caspase-3 and Bax were responsible for neuronal death and were up-regulated in AD. Phyto-carbazoles down-regulated their expressions and prevented apoptosis. ACh, a neurotransmitter essential for processing memory and learning, was decreased in both concentration and function in AD. Decreased levels of ACh could be restored by the AChE and BChE inhibitory activity of phyto-carbazole alkaloids. Overproduction of NO was linked to neuroinflammation, mitochondrial dysfunction and neurotoxicity in NDs. The increased levels of NO were also controlled by phyto-carbazole and plant extracts from the Rutaceae family. Abbreviations: Aβ: Amyloid beta; ACh: Acetylcholine; APP: Amyloid Precursor Protein; AChE: Acetyl Cholinesterase Enzyme; BACE 1: Beta-Secretase 1; Bax: BCL2 Associated X; BChE: Butyl Cholinesterase Enzyme; BDNF: Brain-Derived Neurotrophic Factor; CAT: Catalase; COX-2: Cycloxygenase-2; GSH: Reduced Glutathione; GRD: Glutathione Reductase; GPX: Glutathione Peroxidase; HO-1: Heme Oxygenase-1; iNOS: inducible Nitric Oxide Synthase; IL: Interleukin; NO: Nitric Oxide; NF-kβ: Nuclear Factor Kappa B; Nrf2: Nuclear factor erythroid 2–Related Factor 2; PP2A: Protein Phosphatase 2A; SOD: Superoxide Dismutase; TNF-α: Tumor Necrosis factor-α.