The Agavaceae Endl. Family is distributed in the American continent, among the United States, Central America and the Antilles [1]. In Mexico, approximately 342 species are recognized, and are distributed among eight different genera: Agave L., Beschorneria Kunth, Furcraea Vent., Hesperaloe Engelm., Manfreda Salisb., Polianthes L., Prochnyanthes S. Watson and Yucca L. [2]. The Agave genus is mostly distributed in Mexico, where approximately 75% of these species are located [3].

In Mexico, the genus Agave is of great commercial and cultural importance; several species have been used for centuries as a source of fiber, food, medicine, fuel, shelter, ornament, textiles, compost and alcoholic beverages such as tequila, mezcal and bacanora [4]. More recently, the interest in these species has been growing as potential nutraceuticals, prebiotics, natural sweeteners and biofuels ^[5][6][7][5,6,7].

In traditional medicine, Agave species have been used to treat wounds, sores, trauma, fractures, rheumatoid arthritis, psoriasis, snake bites ^[8][9][8,9], syphilis, scurvy, cancer, limb paralysis, and postpartum abdominal inflammation, as well as being used as diuretics and laxatives [10]. They have also been employed to treat diseases of bacterial etiology such as gastrointestinal and wound infections, urologic disorders, and dysentery as well as cancer, diabetes and hypertension [11].

There are several reports indicating that Agaves have a variety of medicinal properties such as antioxidant, antibacterial [11], anticancer [12] and anti-inflammatory ^[13][14][13,14] activities; at least one study reports an anti-neuroinflammatory effect [15]. Since the process of neuroinflammation can be a start point of several chronic neurodegenerative diseases ^{[16][17][18][19][20]}[16,17,18,19,20], a huge number of natural products have been investigated regarding their capacity to act as anti-inflammatory agents, especially in the brain. However, the role in neuroinflammation has not been fully investigated for these species.

This section includes background information related mainly to the pharmacology of the extracts of the Agave genus species, as well as some of the isolated compounds. In addition to the species mentioned here, the use of these plants in traditional medicine and their distribution in this country were also included (Table 1). This information demonstrates that the species of the Agave genus are perceived with important properties to reduce inflammation and that this attribute can be used as a point of research that analyzes in detail the anti-neuroinflammatory properties of these species that can be applied in the ailment of chronic degenerative diseases related to this process.

Using the in vitro methods of the free radical 2,2-diphenylpicrylhydrazyl (DPPH) and the 2,20–azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), the antioxidant capacity was measured (as µM of Trolox Equivalents (TE)/g dw)., for the methanolic extract of leaves from A. rzedowskiana (27.4127,41 ± 3.35 µM TE/g dw) > A. ornithobroma > A. schidigera > A. tequilana > A. impressa > A. angustifolia [11].

The A. marmorata Roezl chemical and pharmacological activity studies, showed that the saponin smilagenin-3-O-[β-D-glucopyranosyl (1→2)-β-D-galactopyranoside] (1) inhibited the production and release of nitric oxide induced with lipopolysaccharide (LPS) (EC₅₀ = 5.6 mg/mL, E_max = 101%) [29].

For A. salmiana, it was determined that the culture conditions IN (in vitro plants obtained from the tissue culture laboratory at the multiplication step), EN (ex vitro plants obtained after acclimatization step) and WT (wild-type plants obtained from a natural population) exerted an effect on the total concentration of saponins and phenolic acids in methanolic leaf extracts. They observed an increase of 35 and 40% in the phenolic acids content in the IN and EN plants, respectively, compared with WT. The same pattern was observed in terms of total saponin concentration; IN and EN plants showed a 36- and 29-fold increase in saponin content compared to the WT plants. Antioxidant activity was determined using the oxygen radical absorbance capacity assay. IN had the highest antioxidant activity (369 µmol TE/g dw), followed by EN and WT, (184 and 146 µmol TE/g dw). The IN activity was 2.5-fold and 2.8-fold higher than EN and WT, respectively. However, a correlation between antioxidant activity and total phenolic acids or total saponins was not found [30].

The methanolic extract of A. americana leaves showed a direct correlation between total polyphenol and total flavonoid contents on antioxidant activity. According to their capacity to neutralize the free radical 2,2-diphenylpicrylhydrazyl (DPPH), the best one was that with a high total polyphenol content [31].

A. angustifolia extracts, fractions and a purified compound 3-O-[(6’-O-palmitoyl)-β-D-glucopyranosyl sitosterol (2), isolated from A. angustifolia, have demonstrated an anti-inflammatory effect against the oedema induced in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA) at 0.8 mg/ear. Treatment with A. angustifolia led to a decrease in the concentrations of various pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β) and Interleukin-6 (IL-6) as well as an increase in anti-inflammatory cytokines Interleukin-4 (IL-4) and Interleukin-10 (IL-10) [14].

A. tequilana has been shown to have an immunomodulatory effect in a model of systemic lupus erythematosus that is experimentally induced with pristane (2,6,10,14-tetramethylpentadecane). A. tequilana extract decreased articular inflammation and proteinuria, reduced ssDNA/dsDNA antinuclear antibody titers, reduced IL-1β, IL-6, TNF-α, Interferon-γ (IFN-γ) levels and increased IL-10. The phytochemical analysis of A. tequilana extracts revealed the presence of β-sitosterol glycoside, phytol, octadecadienoic acid-2,3-dihydroxypropyl ester, stigmasta-3,5-dien-7-one, cycloartenone and cycloartenol ^[32][33][34][32,33,34]. Aqueous extract and acetonic fractions of this plant, administered in mice (50 mg/kg) with hypertension induced by AGII, showed the plant’s capacity to diminish that condition, and also provoked a significant decrease in IL-1β, IL-6 and TNFα kidney levels induced by AGII. A. tequilana methanolic fraction showed TNFα levels in the kidney similar to the baseline treatment [35].

The saponin (1) isolated from A. marmorata, evaluated on a culture of RawBlue cell line, was capable of inhibition of NF-κB expression (EC₅₀ = 0.086 mg/mL, E_max = 90%), [29].

Dry extracts from decoctions of A. intermixta leaves (300 and 500 mg/kg p.o.) showed potent in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema with a 50.13 ± 3.8% edema inhibition, meanwhile in an assay of TPA-induced ear edema, the topical administration of A. intermixta leaves decoctions (3 and 5 mg/ear) significantly inhibited oedema (50%) compared to the control group [36].

The aqueous extract of A. americana was shown to contain terpenoid compounds and steroidal saponins with anti-inflammatory properties, including agavasaponin E (3) and agavasaponin H (4), hecogenin (5) and tigogenin (6) ^{[37][38][39][40][41][42][43]}[37,38,39,40,41,42,43]. Using the carrageenan-induced oedema model, the aqueous extract (39 µg/kg) from A. americana and a sapogenin-enriched fraction extract (hecogenin and tigogenin) showed anti-inflammatory effects, with 50% and 70–100% inhibition of oedema, respectively [37]. A. americana hydroalcoholic extract (100, 200 and 400 mg/Kg) caused a significant concentration-dependent reduction in paw oedema [43].

The pharmacologic effect of cantalasaponin-1, a saponin isolated from the species A. americana, A. barbadensis [44] and Furcraea selloa var. marginata [45], was evaluated on TPA-induced auricular oedema, showing a dose-dependent inhibitory effect of up to 90% at the highest dose of 1.5 mg/ear [13].

It should be noted that in the resviearch w carried out in the literature, there is only one report about anti-neuroinflammatory activity to the genus Agave, specific to A. americana  and the compound cantalasaponin-1. In this researchstudy, A. americana (125 mg/Kg) and cantalasaponin-1 (5 and 10 mg/kg) reduced brain concentration of LPS-induced proinflammatory cytokines IL-6 and TNF-α. Cantalasaponin-1 increased the brain concentration of the anti-inflammatory cytokine LI-10 [15].

The anticancer activity of linear inulin-type fructan (ITF) prebiotics from A. angustifolia play a significant role in the prevention of colorectal cancer. This was evaluated by using a culture of the human colon cancer cell line Caco-2 (colorectal adenocarcinoma), in the Simulator of Human Intestinal Microbial Ecosystem model. The proximal, transverse and distal vessels were used to investigate fructan fermentation throughout the colon to assess the alterations of the microbial composition and fermentation metabolites (short chain fatty acids and ammonia). The influence on bioactivity of the fermentation supernatant was assessed by MTT (viability assay), Comet (DNA damage assay) and transepithelial electrical resistance (TER), respectively. A. angustifolia fructans significantly increased the population of bifidobacteria, short-chain fatty acid levels and transepithelial electrical resistance while decreasing ammonia levels. This indicates a protective effect on the function of the intestinal barrier, which is an important aspect in the pathology of colon cancer [46].

Five saponins isolated from A. fourcroydes methanolic leaves extract were evaluated to determine cytotoxic activity by fluorometric microculture cytotoxicity assay (FMCA). A new steroidal saponin, elucidated as chlorogenin 3-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)-{β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-(1→2)}-β-D-glucopyranosyl-(1→4)-beta-D-galactopyranoside], along with four known saponins including furcreastatin, chlorogenin 3,6,-di-O-β-D-glucopyranoside and tigogenin3-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)-{β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-(1→2)}-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside] showed strong cytotoxicity against HeLa cells with IC₅₀ values of 13.1, 5.2, and 4.8 µg/mL, respectively [47].

A smilagenin di-glycoside elucidated as (25R)-5β-spirostan-3β-ylO-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside and isolated from A. utahensis Engelm showed cytotoxicity against HL-60 cells with an IC₅₀ value of 4.9 µg/mL, inducing apoptosis through a marked caspase-3 activation [48]. Steroidal saponins isolated from A. utahensis showed moderate cytotoxic activity against HL-60 cells at 20 µg/mL in contrast to the control, etoposide [49]. The spirostanol saponin AU-1 isolated from A. utahensis, caused a transient increase in cyclin-dependent kinase inhibitor (CDKI) p21/Cip1, through the upregulation of the miRNAs miR-34 and miR-21. AU-1 stimulated p21/Cip1 expression without exerting cytotoxicity against different types of carcinoma cell lines (human renal adenocarcinoma-derived ACHN cells and human hepatocellular carcinoma HepG2 cells). In renal adenocarcinoma ACHN cells, AU-1 transiently elevated the expression level of p21/Cip1 protein without marked increases in p21/Cip1 mRNA levels. Rapid and transient increases in miR-34 and miR-21, known to regulate p21/Cip1, were observed in AU-1-treated cells [50].

Concentrated Agave Sap (CAS) obtained from 18 different Mexican states, showed an antiproliferative effect on the culture of cancer cells since it significantly reduced cell viability to 80 % when tested at a concentration of 75 μg/mL on HT-29 (HTB-38), a cellular line with epithelial morphology isolated from colorectal adenocarcinoma. Agave sap also had apoptotic activity on HT-29 (IC503.8 ± 1.3 mg/mL) and NIH-3T3, which are embryonic mouse fibroblast, (IC508.4 ± 1.0 mg/mL) cell lines. The activities found were attributed to the main saponins detected in CAS, including kammogenin and manogenin [12].

The n-butanol extract from inflorescences of A. schotti Engelm was active against Walker carcinoma 256 (intramuscular) tumor system (5WM). Activity was detected in Sprague rats at a level of 7% T/C (Test Control; when the degree of screening activity is significantly greater than the minimum values: ≥125 for survival systems or ≤42 for tumor-weight inhibition) at 75 mg/kg and 28% T/C at 37.5 mg/kg, induced by the saponin-rich fraction separated from the n-butanol extract. Six saponins were isolated, the fourth being the most active against the 5WM tumor system (17% T/C at 65 mg/kg and 22% T/C at 33 mg/kg). Antitumor activity of the system was defined as a percent T/C value of less than 60 in a satisfactory dose response test [51].

Methanolic extract of A. tequilana leaves had antibacterial activity against Pseudomona aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 strains (Minimal Inhibitory Concentration of 5 mg/mL) and the evaluation was carried out using the broth microdilution method. These results were associated with the presence of metabolites like tannins, alkaloids, flavonoids, and saponins [11]. A. tequilana syrup at 50% (w/v) inhibited Bacillus subtillis 168 and E. coli DH5 growth. The bacteriostatic activity was attributed to the high sugar content and high viscosity [52].

The A. americana methanolic leaf extract induced a potent cytotoxic effect against MCF-7 (breast carcinoma) and Vero (African green monkey kidney) cell line. IC₅₀ values were found to be 546 and 1854 μg/mL respectively by the SRB (determination of total cell protein content by sulphorhodamine B) assay [53].

It has been established that obesity is associated with chronic inflammation, and it has been demonstrated in animal models that A. tequilana fructans intake induced a decrease in body mass index (35.3 kg/m² to 33.0 kg/m²), total body fat percentage (38 to 20%), and also in triglyceride levels (167.4 to 107.9 mg/dL p < 0.05), in obese individuals [54].

In addition, the aqueous extract of A. salmiana leaf (100 mg/Kg) has anthelmintic properties, strongly reducing H. gallinarum worm egg counts and worms [55]. Hecogenin (5) (90 mg/Kg), a steroid saponin isolated from A. salmiana leaves, showed anti-ulcer properties in ethanol- and indomethacin-induced gastric ulceration. The gastroprotection mechanism of hecogenin was K-ATP channel dependent [56]. In another study, the depressive behavior induced by reserpine (2 mg/kg, o.p.) was reversed by hecogenin (5 and 10 mg/kg), since it decreases the immobility time compared to the control group (Tween 80/4%) similarly to imipramine (10 mg/Kg) [57].

Magueyosides A, B, D and E isolated from the hydroalcoholic extract of A. offoyana flowers, showed phytotoxic activity at concentrations above 100 µM. They significantly inhibited Lactuca sativa L. root growth (IC₅₀ 88.4µM, 104.3 µM, 131.2 µM and, 101.6 µM, respectively) compared to the commercial herbicide Logran^® (523.7 µM). At the same time, saponin concentrations below 33 µM enhanced root growth [1].

Two saponin-enriched fractions (SFs) obtained through the best traditional extraction method (ethanol:water 8:2) and the best new method (n-butanol:water 1:1) from A. tequilana, A. salmiana, A. angustifolia, A. furcroydes, A. hookeri, A. inaequidens, A. marmorata and A. atrovirens leaves exhibited some selective phytotoxic activity against weeds from the Standard Target Species (STS) Solanum lycopersicum (tomato), Lactuca sativa (lettuce) and Lepidium sativum (cress), as well as on two harmful weed species for agricultural crops Lolium perenne (perenne ryegrass) and Echinochloa crus-galli (barnyardgrass). The researcheuthors mentioned that the saponins from the leaves of these species could be a potential source of ecoherbicides [58].

The insecticidal and repellent activity of A. americana methanolic leaf extract was also assessed either by topical application, treated filter-paper methods or repellent bioassays against Sitophilus oryzae adults. The activity was attributed to the main identified compounds (flavonoids and saponins) permeating the insect’s cuticle [59].

The steroidal saponins Agamenoside G, degalactotigonin, cantalasaponin 1, (25R)-5α-spirost-3β-hydroxy-12-oxo-3-O-β-D-glucopyranosyl-(1-2)-[β-D-xylopyranosyl-(1-3)]-β-D-glucopyranosyl-(1-4)-β-D-galactopyranoside, deltonin, and dioscin isolated from A. americana, showed antifungal activity against Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, Cryptococcus neoformans ATCC 90113, and Aspergillus fumigatus ATCC 90906 [60].