Evidence-Based Complementary and Alternative Medicine

Review Article

Recent Trends in Pharmacological Activity of Alkaloids in Animal Colitis: Potential Use for Inflammatory Bowel Disease

Table 1

Summary of alkaloids effects in experimental colitis models.


Substance (class) and source	Experimental model	Results	Reference

(±)-8-Acetonyldihydrocoptisine (Isoquinoline) Derivative of coptisine, encountered in Coptis sp., Corydalis sp.	C57BL/6J mice DSS	body weight loss ↓ DAI ↓ colon length shortening	[61]

14-O-Acetylneoline (Diterpenoid) Aconitum laciniatum	C57BL/6 mice TNBS	↓ body weight loss ↓ clinical score ↓ piloerection and mobility score ↓ faecal consistence score ↓ macroscopic damage score ↓ colon length decrease ↓ histological injury ↓ INF-γ secretion	[62]

14-O-Veratroylpseudaconine (Diterpenoid) Aconitum laciniatum	C57BL/6 mice TNBS	inflammation (body weight loss)	[62]

Berberine (Isoquinoline) Berberis vulgaris, B. aquifolium, Coptis chinensis, Coptis japonica, Hydrastis canadensis, Mahonia aquifolium,Phellodendron amurense	Sprague-Dawley rats TNBS	↑ body weight ↓ macroscopic damage score ↓ histological damage score ↓ MPO activity and IL-8 production	[63]
	C3H/NeH mice C3H/HeJ mice TNBS	↓ body weight loss and macroscopic damage score ↓ MPO activity, iNOS, MDA, and 4-HNE levels ↓ IL-1β, TNF-α, and IL-6 levels ↑ IL-10 and GSH levels, SOD, and CAT activity	[64]
	Sprague-Dawley rats TNBS	↓ colon index and ulcerative area ↓ TNF-α levels in colon tissue ↓ NF-κB expression in colon tissue = TLR4 expression in colon tissue = LBP level in colon tissue ↓ LBP level in LPS treated cells (HT29 cells) = PGE₂ level in LPS treated cells (HT29 cells) ↓ TNF-α level in LPS treated cells (HT29 cells)	[56]

Berberine (Isoquinoline) Berberis vulgaris, B. aquifolium, Coptis chinensis, Coptis japonica, Hydrastis canadensis, Mahonia aquifolium, Phellodendron amurense	Wistar rats Acetic acid	↓ lesion score and ulcerative area ↓ colon weight/length ratio ↓ histopathological damage ↓ colitis index and ulcer index	[65]
	C57BL/6 mice DSS	↓ body weight loss ↓ inflammation score ↓ MPO activity ↓ TNF-α, INF-γ, IL-17, and KC levels ↓ TNF-α levels in colonic macrophages ↓ IκB degradation, ERK1/2, and p38 activation in colonic macrophages and epithelial cells	[66]
	BALB/c mice DSS	↓ body weight loss ↓ spleen weight ↑ thymus weight ↓ blood hemoglobin levels reduction ↓ colonic MPO activity and MDA levels ↓ INF-γ and IL-12 in splenic lymphocyte production ↑ IL-10 and IL-4 in splenic lymphocyte production	[67]

Berberine (Isoquinoline) Berberis vulgaris, B. aquifolium, Coptis chinensis, Coptis japonica, Hydrastis canadensis, Mahonia aquifolium, Phellodendron amurense	C57BL/6 mice DSS	↓ body weight loss ↓ colon length decrease ↓ lymphocytes infiltration ↓ INF-γ and IL-17 secretion (acute phase) Dopamine D1 and D2-like receptors antagonism ↓ INF-γ, TNF-α, and IL-6 secretion in splenic lymphocytes and peritoneal macrophages ↓ TNF-α, IL-6, IL-12, and TGF-β secretion in bone marrow dendritic cells (BMDC) ↑ IL-1β secretion in BMDC cells	[68]
	C57BL/6 mice DSS	↓ body weight loss ↓ stool consistence and bleeding scores ↓ DAI and histological injury score ↓ colon length decrease ↑ occludin, IL-4, IL-10, and Foxp3 expression ↓ IL-17, IL-6, IL-23, TNF-α, T-bet, ROR-γt expression, and STAT3 activation ↓ Th17 cells infiltration	[69]

Boldine (Isoquinoline) Peumus boldus	Balb/c mice DSS	↓ DAI and histological damage ↑ colon length and ↓ spleen weight ↓ MPO activity and MDA content in colon ↑ SOD and CAT activities in colon ↓ TNF-α, IL-6, IL-17, CD68⁺, and NF-κB expression and pSTAT3 activation in colon ↑ IκB-α expression in colon ↓ NF-κB expression in nucleus of LPS-treated RAW 264.7 cells	[70]

Caffeine (Purine) Coffea arabica, Cola acuminata, Ilex paraguariensis, Paullinia cupana	C57BL/6 mice DSS	↓ body weight loss ↓ clinical and histological scores ↓ tissue F4/80, CD4 and C11b positive cells and bacteria number ↓ TNF-α, INF-γ and IL-17b levels ↑ IL-10 and IL-4 levels ↓ AMCase and CHI3L1 expression ↓ Akt activation	[71]

Cavidine (Isoquinoline) Corydalis impatiens	Kunming mice Acetic acid	↓ body weight loss and mortality ↓ DAI ↓ macroscopical and histological scores ↓ colon weight/length ratio ↓ NF-κB, TNF-α, and IL-6 expression in colon ↓ TNF-α and IL-6 serum levels ↓ MPO activity and MDA levels in colon ↑ SOD activity and GSH levels in colon	[72]

Dihydrocoptisine (Isoquinoline) Derivate of coptisine, encountered in Coptis sp., Corydalis sp.	C57BL/6J mice DSS	↓ body weight loss ↓ colon length shortening ↓ DAI and macroscopic damage score ↓ histological damage	[61]

EM012 (reduced brominated derivative of noscapine) (Isoquinoline) Derivative of noscapine, encountered in Papaver somniferum	C57BL/6J mice DSS	↓ body weight loss ↓ colon length shortening ↓ histological damage ↓ MPO activity in colon ↓ IL-1β, IL-6, and INF-γ levels in colon	[73]

Fumigaclavine C (Indole) Aspergillus fumigatus	BALB/c mice TNBS	↓ macroscopic damage ↓ histological damage scores ↓ body weight loss ↓ mortality ↓ IL-1β, IL-2, IL-12α, IFN-γ, TNF-α, and MMP-9 mRNA levels ↓ IL-2 and IFN-γ level ↓ MMP-9 activity = COX-1	[74]

Hypaconitine (Diterpenoid) Aconitum carmichaeli	Sprague-Dawley rats TNBS	= colon index = ulcerative area ↓ LBP level in colon tissue = TNF-α levels in colon tissue ↓ NF-κB and TLR4 expression in colon tissue ↓ LBP and PGE₂ levels in LPS treated cells (HT29 cells) = TNF-α level in LPS treated cells (HT29 cells) ↑ frequency and amplitude of contract in colon and duodenum	[56]

Isatin (Indole) Isatis sp., Calanthe discolor, Couroupita guianensis	Wistar rats TNBS	↓ macroscopic score ↓ GPx and GR activity and ↑ SOD activity and GSH contents ↓ COX-2 expression = COX-1 expression ↓ TNF-α expression ↓ INF-γ and PGE₂ levels ↑ IL-10 levels	[75]

Matrine (Quinolizidine) Sophora sp.	BALB/c mice TNBS	↓ body weight loss ↓ macroscopic and histological damage scores ↓ MPO activity ↓ TNF-α mRNA and protein levels	[76]

Nigakinone (Indolonaphthyridine) Picrasma quassioides	Wistar rats DSS	↓ body weight loss ↓ colon length shortening ↓ DAI ↓ MPO activity ↓ TNF-α serum levels	[77]

NK007 (Phenanthroindolizidine) Derivative of tylophorine, encountered in Tylophora sp.	BALB/c (Tnf-α-luc)-Xen mice DSS (acute colitis)	↓ body weight and colon length loss ↓ TNF-α (luciferase activity) ↓ histological damage	[78]
	C57BL/6 mice DSS (chronic colitis)	↓ DAI and macroscopic damage scores ↓ histological damage, ↓ TNF-α and IL-12 levels ↓ p-p65 (NF-κB) expression
	Wistar rats Acetic acid	↓ DAI and macroscopic damage scores ↓ TNF-α and IL-12 levels and ↓ p-p65 (NF-κB) and p-IκB expression (in vitro)

Oxymatrine (Quinolizidine) Sophora flavescens	Sprague-Dawley rats DSS	↓ DAI and mucosal damage scores ↓ TNF-α and IL-6 serum levels ↓ colonic ICAM-1 and NF-κB expression	[79]
	Sprague-Dawley rats TNBS	↓ body weight loss ↓ looser stool and bloody purulent stool ↓ macroscopic and histological score ↓ NF-κB (p65) expression ↑ 2βAR and β-arrestin-2	[80]
	Sprague-Dawley rats TNBS	Attenuation of colitis (diarrhea, bloody stool, and histopathological changes were analyzed) ↓ β-arrestin-1 and Bcl-2 expression	[81]
	Rats TNBS	Inflammation amelioration ↓ IL-2 levels ↓ NF-κB expression ↑ IL-10 levels	[82]
	C57BL/6 mice DSS	↑ body weight ↓ histological damage score ↓ IL-6 and IL-1β mRNA colonic levels	[83]

Papaverine (Isoquinoline) Papaver somniferum	C57BL/6 mice DSS	= body weight loss ↓ DAI ↓ bleeding and diarrhea ↓ histological damage ↑ venular leukocyte adherence in colon = venular platelets adherence in colon	[84]

Piperine (Piperidine) Piper nigrum, Piper longum	Swiss mice Aceti acid	= histological changes = MPO activity, MDA content, and GSH levels in serum and in colon	[59]
Piperine (Piperidine) Piper nigrum, Piper longum	C57BL/6 mice DSS	↓ body weight loss and diarrhea ↓ colon length decrease ↓ macroscopic and histological scores ↑ PXR, Cyp3a11, Cyp3a13, GSTα1, and MDR1α mRNA expression in colon tissue ↓ ICAM, iNOS, IL-1β, MCP-1, IL-6, IL-10, and TNFα mRNA expression in colon tissue = CCR2 mRNA expression in colon tissue	[85]

Piperine (Piperidine) Piper nigrum, Piper longum	Swiss mice Acetic acid	↓ ulcer area and macroscopic score ↓ colon weight/ length ratio ↓ microscopic score and cell infiltration ↓ MPO activity and MDA content ↑ SOD activity and GSH levels ↓ TNF-α and NO levels ↓ free fat acids levels ↓ histological damage	[86]

Sanguinarine (Isoquinoline) Sanguinaria canadensis, Argemone mexicana	Kunming mice Acetic acid	↓ mortality rate and body weight loss ↓ DAI ↓ macroscopic damage score ↓ histological damage score ↓ IL-6 and TNF-α expression ↓ IL-6, TNF-α serum, and colonic levels ↓ MPO tissue accumulation	[87]

Sinomenine (Isoquinoline) Sinomenium acutum	BALB/c mice TNBS	↓ body weight loss ↓ macroscopic and histological damage scores ↓ MPO colonic activity ↓ TNF-α and INF-γ mRNA and protein expression	[88]
Sinomenine (Isoquinoline) Sinomenium acutum	BALB/c mice TNBS	↓ body weight loss, mortality, and diarrhea ↓ histological damage score ↓ miR-155 in colon tissue ↓ c-Maf, TNF-α, and INF-γ mRNA expression and protein levels in colon	[89]

Skimmianine (Quinoline) Pericarpium Zanthoxyli	Sprague-Dawley rats TNBS	= colon index = ulcerative area ↓ LBP level in colon tissue = TNF-α levels in colon tissue ↓ NF-κB expression in colon tissue ↓ TLR4 expression in colon tissue ↓ LBP level in LPS treated cells (HT29 cells) ↓ PGE₂ level in LPS treated cells (HT29 cells) = TNF-α level in LPS treated cells (HT29 cells)	[56]

Sophocarpine (Quinolizidine) Sophora alopecuroides	C57BL/6 mice DSS	↓ DAI ↓ weight loss ↓ colon length shortening ↓ histological damage score ↓ MPO colonic activity ↓ IL-6 and IL-1β serum levels	[90]

Sophoridine (Quinolizidine) Sophora alopecuroides	C57BL/6 mice DSS	↓ damage scores ↓ plasma haptoglobin ↓ ICAM-1 levels	[91]

Tetrandrine (Isoquinoline) Stephania tetrandra	BALB/c mice DSS	↓ DAI and histological damage score ↓ TNF-α and IL-1β mRNA and protein expression ↓ NF-κB DNA binding activity ↓ MPO colonic activity	[92]

Tryptanthin (Indoloquinazoline) Candida lipolytica, Couroupita guianensis, Isatis tinctoria, Wrightia tinctoria, Strobilanthes cusia	CBA mice DSS	↑ animal survival ↓ colon inflammation (MRI) ↓ thickness of bowel wall (MRI) ↓ intestinal microvasculature damage (MRI)	[93]

W-8 (Tylophorine analog) (Phenanthroindolizidine) Derivative of tylophorine, encountered in Tylophora sp.	BALB/c mice TNBS	↑ Body weight ↑ Colon length ↓ histological damage score ↑ IL-10 and Fox3 mRNA colonic levels ↓ INF-γ and TNF-α mRNA colonic levels	[94]

↓ minor, ↑ major, = similar, when compared with control colitis. abstract accessed. et al. [61] also evaluted the alkaloids 13-Methyldihydrocoptisine, 8-(1-Acetylethenyl)-13-methylcoptisine Chloride, 8-(1-Propionylethenyl)-13-methylcoptisine Chloride, 13-(2,4-Difluorobenzyl)coptisine Chloride, 13-(2,4-Difluorobenzyl)-Dihydrocoptisine, Tetrahydrocoptisine, 8-oxodihydrocoptisine in DSS-induced colitis. They exhibited very weak efficacy or no efficacy in vivo (data not show in original paper).