Table 1.

A summary of pre-clinical and clinical studies on protective effects of genus Boswellia in the neurodegenerative diseases

Protective agent/dose/reference	Study design or experimental model	Main results
B. serrata (45 and 90 mg/kg/day, 2 weeks) (24).	Animal model AD induced by AlCl3 in rat	Elevated ACh, suppressed AChE activity, improved histopathology changes, and reduced Aβ plaques in the hippocampus
B. serrata resin methanolic extract (137.5 mg/kg, 3 months) (25).	Animal model AD induced by AlCl3 in rat	Induced anti-neuro-inflammatory and anti-apoptotic properties indicated by suppression of serum level of AChE, CRP, NF-kB, MCP-1, LTB4, and elevation of brain ACh and Bcl-2. Aβ plaques disappeared
Co-administration of ginger (Zingiber officinale, 216 mg/kg) and B. serrata (45 and 90 mg/kg) (26).	Animal model AD induced by AlCl3 in rat	Improved histopathologic changes and behavior stress tests including activity cage, rotarod, and T- maze as well as restored ACh and AChE level in brain homogenate
Frankincense aqueous extract (50 mg/kg, 42 days) (32).	STZ (1.5 mg/kg/2 μl/side, i.c.v) - induced memory impairment	Evaluation of learning using passive avoidance task and improvement of memory
SHXW essential oil (1, 10, 100 µg/ml) (34).	SH-SY5Y neuroblastoma under Aβ1-42 (25 µM) toxicity	Attenuated Aβ-induced cytotoxicity through inhibition of apoptosis and ROS generation Up-regulated HO-1 and Nrf2 expression and Bcl-2/Bax protein ratio
	Mouse AD models induced by Aβ1-42	Ameliorated cognitive dysfunction in mice associated with reduced p38, c-Jun N-terminal kinases, and tau phosphorylation
Boswellia resin extract (10 µg/ml) (38).	An in vitro PD model induced by MPTP in human dopaminergic SK-N-SH cell-line	Attenuated MPTP-induced neurotoxicity including inhibition of apoptosis
1) B. serrata aqueous extract (0.1 g/kg/day) (47) 2) B. serrata (100 mg/kg/day) (48).	Assessment of cognitive dysfunction in young Wistar rats whose mothers received Boswellia during gestation (3 weeks)	Induced more dendritic segments and branching density in the neurites of CA3 hippocampal cells
Frankinsense aqueous extract (50 and 100 mg/kg, 4 weeks) (49).	Assessment of learning and spatial memory in rats using Morris water maze test method	Facilitated the learning and spatial memory formation as reduction in escape latency and traveled distance
Frankincense aqueous extract (50 and 100 mg/kg) during gestation and lactation periods (50).	Assessment of the frankincense efficacy on memory formation during development of the rat brain	Enhanced memory performance and up-regulated CaMKII and CaMKIV mRNA levels in the hippocampus offspring rats
Frankincense aqueous extract (50 and 100 mg/kg/day, 4 weeks) (54).	Evaluation of the spatial memory parameters by MWM test	Improved spatial learning and memory and up-regulated expression of BDNF but not CREB
Boswellia papyrifera total extracts (300 mg/kg, three times a day) and boswellic acids fraction (100, 200, and 300 mg/kg) (55).	Assessment of spatial memory using MWM task	Enhanced the retention phase of spatial memory proposing the improvement of memory function
Olibanum (100 and 500 mg/kg, 180 days) (59).	Assessment of memory function using methimazole-induced hypothyroidism animal model	Counteracted memory deficit in the Morris water maze test
Ethyl acetate (0.1 mg/kg) and N-butanol (0.1 mg/kg) fractions of B. carterii gum resin (61).	Memory impairments induced by hyoscine-induced	Ethyl acetate fraction was much more significant than other fraction in enhancing the memory ability indicated by the MWM task
Combined administration of M. officinalis and B. serrata (200 and 400 mg/kg) (62).	Spatial memory against cognitive impairment related to scopolamine	Improved memory performance indicated by MWM method
Frankincense hydro-alcoholic extract (50 mg/kg) (67).	Memory loss following LPS administration (1 mg/kg)	Enhanced step-through latency in a passive avoidance task accompanied by reduced TNF-α level in the hippocampus
Aqueous extracts of B. serrata (0.1, 0.5, and 1 g/kg, IP) (71, 72).	Pentylenetetrazol-induced kindled rats were used to study epilepsy and its consequences on memory using shuttle box apparatus and step-through latency method	Improved passive-avoidance learning ability associated with an increase in the number of pyramidal neurons and dendritic spines in CA1
B. serrate aqueous extract (100 mg/kg/d, for 8 weeks) (74).	Age-related morphological changes of hippocampal granule cells and concomitant cognitive deficits in escape latency and swimming distance	Enhanced dendritic complexity in the dentate granule cells and spine density associated with improvement of spatial learning capability
A tablet containing B. serrata and Melisa officinalis extract (290 and 27 mg) (75).	A randomized, parallel, double-blind, placebo-controlled clinical trial performed among 70 older adults	Improved memory function
Ethanolic extract of B. serrata oleo-gum resin (10, 20, 40, and 80 µg/ml) (79).	Oligodendroglia (OLN-93) cell injury induced by glutamate and quinolinic acid	Attenuated oxidative stress
The extract mixture of Portulaca olerace, Urtica dioica, and B. serrata (200 and 400 mg/kg) (81).	MS model induced by intra-hippocampal injection of ethidium bromide (stereotaxic surgery) in rats	Induced neurogenesis and memory improvement in the shuttle box test
Capsule containing B. papyrifera (300 mg, twice a day, 2 months) (82).	A randomized, double-blind, clinical trial in MS patients	Indicated therapeutic efficacy for cognitive dysfunction as improved visual-spatial memory
Capsule containing B. serrate extract (450 mg twice a day, two months) (83).	A double-blind clinical trial in MS patients with cognitive deficits	Improved cognitive deficits indicated by the improvement of auditory/verbal and visual/spatial memory in brief visuospatial memory test and California verbal learning test
B. serrata hydroalcoholic extract (1.5-6 µg/ml) and AKBA (0.5-2.5 µg/ml) (90).	Ischemia-induced cytotoxicity in PC12 cells following exposure to oxygen/glucose/serum deprivation condition	Increased cell survival and counteracted oxidative stress (ROS, lipid peroxidation, and oxidative DNA damage)
BSE (25, 50, 100 μg/ml) and AKBA (5 μm) (91).	Cell culture model of neurodegeneration induced by glutamate toxicity in PC12 and Neuro-2a cell	Inhibited oxidative damage and apoptotic cell death
B. serrata methanolic extract (50, 100, 250, 500, 1000, and 2000 µg/ml) (93).	In vitro assessment of antioxidant and anti-inflammatory activity	Exhibited DPPH free radical scavenging activity (IC50 = 54.06 µg/ml), ferric reducing power (IC50 = 62.12 µg/ml) stabilization towards human red blood cell membrane stabilization
Boswellia aqueous and ethanolic extracts (125, 250, and 500 mg/kg, IP) and AKBA (50 mg/kg, IP) (94).	An animal model of ischemia, MCAO	Improved neurological deficits and reduced brain infarction volume, neuronal apoptotic cell death accompanied by up-regulation of Bcl-2 and down-regulation of Bax and caspase-3. Reduced oxidative stress (counteracted lipid peroxidation and restored glutathione content and superoxide dismutase activity) in the cerebral cortex
Frankincense aqueous extract (100 and 150 mg/kg, 30 days) (95). 95	MCAO surgery was performed to induce ischemia-reperfusion status	The level of blood-brain barrier (BBB) permeability and stroke-induced brain edema and reduction of infarction volume and neurological impairments
BS (4200 mg/day) during radiotherapy (96).	A prospective, randomized, placebo-controlled, double-blind, pilot trial in cerebral edema following brain radiotherapy	Suppressed the edema volume evaluated by T2-weighted magnetic resonance imaging (MRI)
B. serrata capsules (containing 215 mg gum resin) for 6 weeks (97).	Assessment of effect on neuro-recovery following diffuse axonal injury in a double-blind, randomized, cross-over study	Enhanced the cognitive outcome of patients with diffuse axonal injury
B. serrata (250 and 500 mg/ kg) (98).	Cerebral inflammation after induction of diffuse traumatic brain injury	Attenuated brain edema and disruption of blood-brain-barrier accompanied by improvement of vestibulomotor dysfunction and modulation of IL-1β and IL-10 in the brain tissue

Ach: Acetylcholine; AChE: acetylcholine esterase; Aβ: amyloid Beta; Bcl-2: B-cell lymphoma 2; BDNF: Brain-derived neurotrophic factor; CREB: cAMP response element-binding protein; CRP: C-reactive protein; DPPH: 2,2-diphenyl-1-picrylhydrazyl; IL-10: Interleukin 10; LTB4: Leukotriene B4; MCAO: middle cerebral artery occlusion; MCP-1: Monocyte Chemoattractant Protein-1; MPTP: 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyryridine; MWM: Morris water maze; MS: Multiple sclerosis; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; ROS: reactive oxygen species content; SHXW: SuHeXiang Wan; CaMKII: calcium/calmodulin kinase II