Nauclea sp.

Nauclea latifolia (Rubiaceae)(syn. Sarcocephalus latifolius)
English: Pin cushion tre , African peach, Guinea peach, Sier a Leone peach
French: Scil e maritime, oignon marine, medicinal squil
African vernacular names:
Hausa: Tafashiya, tashiyaigia (medicinal y useful bark) Igbo: Ubuluinu
Trade name: Opepe

The plant
Nauclea latifolia is an evergre n multi-stemmed shrub or a tre ; it grows up to an alti ude of 20 m. It is widespread in the humid tropical rainforest zone or in savan ah wo dlands of West and Central Africa. Thre other elated species Nauclea. pobeguini, N. diderichi , and N vanderguchti are forest re s. N. diderichiis planted in Omo forest reserve, Nigeria. In the folk medicine the species N. diderichi and N. orientalis are used in the same way as N. latifolia. Nauclea latifolia has an open canopy and terminal spherical head lined cymes of white flowers. The flowers are joined with their calyces. The fruit is syncarp. The tre is flowering from April to June. The fruits are ripening from July to September. Babo ns eat hem and disperse the se ds. Livestock eat sho ts and leaves. The fruits are edible, to . The wo d of N. latifolia (Opepe wo d) is termite resistant and is used as live stakes in farms. Plant parts used The leaves, the stem, the stem bark, the ro t

Constituents
Alkaloids:
Al plant parts of the Nauclea species are a rich source of monoterpene indolalkaloids. There is a lot of works. In the abundance of these works not alpublications can be cited, only such ones about he indole alkaloids from the bark of N. orientalis (19), and about he naucleamides A - E in the bark and woud of N. latifolia (15). The indole alkaloid strictosamine has be n found in the rout, the leaves andstem bark (15). In the water soluble extract of N. latifolia stems seven indole alkaloid glycosideswere isolated, among them swerosid and loganin. From the bark and from the wo d the alkaloids naucleactonine A and B, naucleficine and nauclefidine were isolated (18). 
In the leaves of N. orientalis strictoseamide, vincoseamid and their glycosides10-hydroxy-strictosamide and 6`-O-acetylstrictosamide could be found (6). 
Saponins
The basic compound of the most saponines is quinovic acid, a five-cyclictriterpene. The structural dif erence betwe n the single saponines consists in glycosidation; it means the interglycosidic linkage with sugars in a different steric conformations. In a methanolic extract from N. diderichi bark eleven single saponines could be found. The quanti ative determination is 4.62 % of the extract and 0.18 % of the bark. Two of such saponines are: (1) quinovic acid-3-O-alpha-L-rhamnosy l(281) beta-D-glucopyranosyl ester and (2) quinovic acid-3-O-(beta-D-glucopyranosyl (12)
beta-D-glucopyranosid) (1 ). 
Further compounds
In the leave extracts from plants in Kinshasa; DR Congo, active polyphenols werefound (16). 

Traditional uses
In West and South Africa infusions and decoctions of the bark and leaves are used for the treatment of stomach pains, fever, diar hoea, and against parasites, like nematodes in men and animals, and tropical diseases like malaria. In Kano (Nigeria) N. latifolia is used as a chewing stick and as a remedy against stomach ache and tuberculosis (3). In Ivory Coast infusions and decoctions from stems and ro ts of N. latifolia are used against malaria by tradit onal healers (2). In West and Central Africa N. diderichi is used for its insecticidal and antiparasit c properties. In Gabon, Congo and Nigeria infusions of leaves and bark are employed against fevers (4). In Kinshasa, DR Congo extracts and preparations together with other plants are ap lied against diar hoea (16). Results of experimental studies

Antibacterial activity
The root bark of N. latifolia col ected from Falgore Forest in Kano, Nigeria was extracted by aqueous ethanol and divided in five fractions. Fractions containing alkaloids were very active on eleven bacterial and two fungal strains. The bioas ay was done with two standard bacterial susceptibil ty as ays ADM and MDM (3). No test strains of bacteria, neither Gram posit ves nor Gram negatives, were susceptible to the hot water extract of N. latifolia (13). 

Antimalarial activity in vitro
Aqueous extracts -infusions and decoctions- from stems and ro ts of N. latifolia were tested in vitro in two Plasmodium falciparum strains, FcB1-Colombia (chloroquine resistant) and a Nigerian strain (chloroquine-resistant) ac ording to the methods used by tradit onal healers. The in vitro activity was as es ed visual y and by a radioactive method. The IC50 values ranged from 0.6-7.5 µg/ml of the init al dry weight of the plant. Here harvesting time influenced the antiparasitical activity of the plants, because activity of batch 1 -harvested in September- was half that from batch 2 -harvested four months later. Ir espectively of the extract origin, stem or o t, the IC50 values were similar forinfusions or decoctions. In al batches ro t-decocted extracts brought he best results. N. latifolia extracts inhibited es ential y the final developmental stages of the parasites (2).3 Two novel tetrahydro-fl-carboline monoterpene alkaloid glycosides, naucleaorine and epimethoxy-naucleaorine, isolated by chloroform from the dried stem of N. latifolia, strictosidine lactam, and oleanolic acid showed moderate in vitro activit es against Plasmodium falciparum (8). In the Democratic Republic of Kongo crude extracts of the stem bark of N. pobeguini were tested for antimalarial activity in vitro against Plasmodium
falciparum and in mice infected with P.berghei. Dichloromethane extracts from the stem bark of N. pobeguini were found to be very active with an IC50 value 1< µg/ml. The IC50 of the water extract was 5.3 µg/ml. The aqueous extract produced a lower but significant inhibit on of parasitaemia (60-80 %) (12). Out of thirty thre plants, commonly used in West ropical Africa by traditional healers for the treatment of malaria N. latifolia showed a go d antiplasmodial activity and a weak toxicity. The ethanolic extract, obtained by decoction was evaluated in vitro against he chloroquine-resistant FcB1 strain of Plasmodium falciparum. Cytotoxicity was evaluated on the human MRC-5 and the rat line L- 6 cel lines (20). 

Further antiparasitic activity
In Africa leishmaniosis is a disease with high incidence. Because of the lack of medicines people rely on tradit onal treatment with N. diderichi . Four quinovic acid glycosides and cadambine acid isolated from the bark of N. diderichicol ected in the vicinity of Librevil e, Gabon revealed a strong antileishmanial activity with IC50 =1 µM. The toxicity against human cel s (IC5 10 µM)se med to be weak (4) in order to ensure adequate drug release (5). In Kinshasa, polyphenols from leaves inhibited Entamoeba histolytica growth with MAC <10 µg/ml (16). Anthelmintic activity
In Bauchi, Bauchi State the anthelmintic ef icacy of water extract from N. latifolia stem bark was studied in 30 she p with natural parasit c gastroenteritis caused by mixed nematode species. Infected she p were treated with stem bark extract (40 , 80 , 160 mg/kg) for five consecutive days. A control group was treated with a single dose of 5 mg/albendazol per os once at he day 0, the standard anthelminthic. The faecal samples, collected daily in the morning were evaluated for the presence of worm eg s by salt flotation technique. After five days of the treatment with 40 , 80 , 160 mg/kg the extract reduced the counted nematode eg s with 69.8, 82.4 and 93.8 %, respectively. The highest ested dose, 60 mg/kg for five days was comparable to the single dose of albendazol 5mg/kg on day 0. In the infected she p the HB concentrations after five days treatment
increased betwe n 20 or 30 %, the leucocytes decreased significantly in the extract and albendazol treated groups when compared to pre-treatment values. These in vivo results fol ow the results of an in vitro study where eg hatching of Strongyloides nematodes was prevented significantly. The authors conclude that the extract inhibits the protein synthesis in the parasite eg s. These results could be the pharmacological basis for the folkloric medicinal ap lication of this plant (14). In Nigeria extracts (10p m) of N. latifolia kil 50 % of brine shrimp nauplia. Against ascaris IC50 values are brought by doses of 2, 5, 10 µg/L. Nematode glutathione-S-transferases are potential drug targets (7). 

Neuropharmacological and biochemical effects
The aqueous extract of N. latifolia ro t bark significantly decreased the spontaneous motor activity in mice and prolonged pentobarbital sle ping time in4 rats dose-dependently. The extract also remarkably at enuated the intensity of apomorphine-induced stereotypy dose-dependently in mice, but had no effect on motor co rdination in the rotarod. The authors conclude that psychoactive substances are present in the aqueous extract (1). In Kinshasa, DR Congo polyphenolic extracts from leaves of N. latifolia inhibited 70 % acetylcholine and/or KCl solution-induced contractions on isolated guinea-pig ileum (16). Mol uscicidal activity
Methanol and water extracts of 25 Nigerian plants used for different medicinal and domestic purposes were tested for mol uscicidal activity. Between them N. latifolia was found active and LC50 was determined with up er and lower fiduciallimits, but without any singular values in the summary cited. The authors recommend that he toxic ef ects of these extracts should be known in order to use such plants in right concentrations in fish ponds (9). 

Antimalarial tablets
There is a first, preliminary information about he development of a suitable tablet dosage form for a medicament against malaria. Studies were done with the water extract of N. latifolia. It was oven dried and the mechanical properties were determined. The tablets produced had good mechanical properties, like hardnes increasing with compres ion pres ure. But he friabil ty decreased and the disintegration was po r. A disintegrating material should be ne ded to be included in the formulation of the tablets (5). 

Toxicity
The alkaloid rich extracts from N. latifolia were evaluated in vitro and in vivo systems for toxicity and genotoxicity. They can interact in vitro with DNA of bacteria and mammalian cel s, leading to G2-M cel cycle ar est and heritable DNA-damage. In liver, kidney and blo d cel s they induce single-strand breaks (17). No significant oxic ef ect was observed for the dried water extract of N. pobeguini, the LD50 was >5g/kg. Neither this extract af ected the serum concentrations of GPT or the blo d concentrations of creatinine and urea, but it increases the serum concentrations of GOT (12). 

Evaluation
The main compounds of Nauclea plants are the toxic indole alkaloids and saponines. These are big molecules which only can be solved by organic
solvents. Water extract do this only in very lit le amounts and solve mostly the non-toxic common components of the plant. Therefore alcoholic extracts must be viewed as very toxic. The water extract contains mainly polyphenols and saponines. It is les dangerous. But here no recommendation can be given for use with men or in animals, nor for water or for alcoholic extracts. Because of its toxicity al uses of Nauclea latifolia with men and animals must be advised against. Nauclea latifolia and related species5 for uses with men and animals 

References Nauclea
1. Amos S, Ab ah J, Chindo B et al.(20 5) Neuropharmacological ef ects of the aqueous extract of Nauclea latifolia ro t bark in rats and mice J Ethnopharmacol 97,1: 53-7
2. Benoit-Vical F,Valentin A,Cournac V et al. (19 8) In vitro antiplasmodial activity of stem and ro t extracts of Nauclea latifolia S.M. (Rubiaceae) J Ethnopharmacol 61: 173- 8
3. De ni YY, Hus ain HSN (19 1) Scre ning for antimicrobial activity and for alkaloids ofNauclea latifolia J Ethnopharmacol 35: 91-6
4. DiGeorgio C, Lamidi M, Delmas F et al. (20 6) Antileishmanial activity of quinovic acid glycosides and cadambine acid isolated from Nauclea dider ichi Planta Med 72:1396-1402
5. Emeje MO, Isimi CY, Oqua DA, Kunle OO (20 5) Some compaction characteristics of the hot water leaf extract of Nauclea latifolia : A potential malaria agent J Herb Pharmacother 5,4: 23-30 PubMed 16 3 5965
6. Erdelmeier CAJ, Wright AD, Orjala J et al. (19 1) New indole alkaloid glycosides from Nauclea orientalis Planta Med 57: 149-52
7. Fakae BB, Campbel AM, Bar et J et al. (20 0) Inhibit on of glutathione-S-transferases (GSTs) from parasit c nematodes by extracts from tradit onal Nigerian medicinal plantsPhytother Res 14,8: 630-4 PubMed 1 1 40 1
8. He ZD, Ma CY, Zhang HJ et al. (20 5) Antimalarial consti uents from Naucleaorientalis (L.) Chem Biodevers 2,10: 1378-86 PubMed 17191939
9. Kela SL, Ogunsusi RA, Ogbogu VC, Nwude N (1989) Scre ning of some Nigerian plants for mol uscicidal activity Rev Elev Med Vet Pays Trop 42,2 :195-202 PubMed 2626572
10. Li T, Wang WJ, Hu X (20 5) Study on fingerprint of unfinished product of Nauclea injection Zhong uo Zhong Yao Za Zhi 30,15: 1 56-8 PubMed 1620 168 1 . Lamidi M, Ol ivier E, Faure R et al. (19 5) Quinovic acid glycosides from Nauclea dider ichi Phytochem 38,1: 209-12
12. Mesia GK, Tona GL, Penge O et al (20 5) Antimalarial activit es and toxicit es of thre plants used as tradit onal remedies for malaria in the Democratic Republic of Congo:Croton mubango, Nauclea pobeguini and Pyracantha staudti An Trop Med Parasitol 9 ,4: 345-57 PubMed 1594 9182
13. Okoli AS, Iroegbu CU (20 4) Evaluation and extracts of Anthocleista djalonensis, Nauclea latifolia and Uvaria afzali for activity against bacterial isolates from cases of non-gonococ al urethrit s J Ethnopharmacol 92,1: 135-4
14. Onyeyil PA, Nwosu CO, Amin JD, Jibike JI (20 1) Anthelmintic activity of crude aqueous extract of Nauclea latifolia stem bark against ovine nematodes Fitoter 72: 12- 21
15. Shigemori H, Kagata T, Ishiyama H et al. (20 3) New monoterpene alkaloids from Nauclea latifolia Chem Pharm Bul 51,1: 58-61
16. Tona L,Kambu K,Ngimbi N et al. (20 0) Antiamoebic and spasmolytic activit es of extracts from some antidiar hoeal tradit onal preparations used in Kinshasa, Congo Phytomedicine 7,1: 31-8 PubMed 1078248
17. Traore F, Gasquet M, Laget M et al. (20 0) Toxicity and genotoxicity of antimalarial alkaloid rich extracts derived from Mitragyna inermis O. Kuntze and Nauclea latifolia Phytoter Res 14,8: 608-1 PubMed 1 1 39 7
18. Xuan WD, Chen HS, Du IL et al. (20 6) Two new indole alkaloids from Nauclea officinalis J Asian Nat Product Res 8,8: 719-2 PubMed 171456 06
19. Zhang Z, ElSohly HN, Jacob MR et al. (20 1) New indole alkaloids from the bark of Nauclea orientalis J Nat Prod 64,8: 1-5
20. Zirihi GN, Mambu L, Guede-Guinea F et al. (20 5) In vitro antiplasmodial activity and cytotoxicity of 3 West African plants used for treatment of malaria J Ethnopharmacol 98,3: 281-5



Nauclea latifolia Smith (Rubiacea) is a small tree, found in tropical areas in Africa. It is used in traditional medicine to treat malaria, epilepsy, anxiety, pain, fever etc.

The aim of this study was to investigate the effects of Nauclea latifolia roots decoction on the peripheral and central nervous systems and its possible mechanisms of action.

Materials and methods
The analgesic investigation was carried out against acetic acid-induced writhing, formalin-induced pain, hot-plate and tail immersion tests. The antipyretic activity was studied in Brewer’s yeast-induced pyrexia in mice. Rota-rod test and bicuculline-induced hyperactivity were used for the assessment of locomotor activity.

Results
Nauclea latifolia induced hypothermia and had antipyretic effects in mice. The plant decoction produced significant antinociceptive activity in all analgesia animal models used. The antinociceptive effect exhibited by the decoction in the formalin test was reversed by the systemic administration of naloxone, Nω-L-nitro-arginine methyl ester or glibenclamide. In contrast, theophylline did not reverse this effect. Nauclea latifolia (antinociceptive doses) did not exhibit significant effect on motor coordination of the mice in rota-rod performance. Nauclea latifolia protected mice against bicuculline-induced behavioural excitation.

Discussion and conclusion
Overall, these results demonstrate that the central and peripheral effects of Nauclea latifolia roots decoction might partially or wholly be due to the stimulation of peripheric opioid receptors through the action of the nitric oxide-cyclic GMP-ATP-sensitive K+ (NO/cGMP/ATP)-channel pathway and/or facilitation of the GABAergic transmission.

Enkele onderzoeken

Antipyretic and antinociceptive effects of Nauclea latifolia root decoction and possible mechanisms of action.
Taïwe GS, Bum EN, Talla E, Dimo T, Weiss N, Sidiki N, Dawe A, Moto FC, Dzeufiet PD, De Waard M.
Pharm Biol. 2011 Jan;49(1):15-25. doi: 10.3109/13880209.2010.492479. Epub 2010 Sep 7.

Nauclea latifolia Smith (Rubiaceae) exerts antinociceptive effects in neuropathic pain induced by chronic constriction injury of the sciatic nerve.
Taïwe GS, Bum EN, Talla E, Dimo T, Dawe A, Sinniger V, Bonaz B, Boumendjel A, De Waard M.
J Ethnopharmacol. 2014;151(1):445-51. doi: 10.1016/j.jep.2013.10.068. Epub 2013 Nov 18.

Pharmacological evidence favouring the use of Nauclea latifolia in malaria ethnopharmacy: effects against nociception, inflammation, and pyrexia in rats and mice.
Abbah J, Amos S, Chindo B, Ngazal I, Vongtau HO, Adzu B, Farida T, Odutola AA, Wambebe C, Gamaniel KS.
J Ethnopharmacol. 2010 Jan 8;127(1):85-90. doi: 10.1016/j.jep.2009.09.045. Epub 2009 Sep 30.

Anticonvulsant, anxiolytic, and sedative properties of the roots of Nauclea latifolia Smith in mice.
Ngo Bum E, Taiwe GS, Moto FC, Ngoupaye GT, Nkantchoua GC, Pelanken MM, Rakotonirina SV, Rakotonirina A.
Epilepsy Behav. 2009 Aug;15(4):434-40. doi: 10.1016/j.yebeh.2009.05.014. Epub 2009 Jun 27.

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