Potential Application of Yokukansan as a Remedy for Parkinson’s Disease

Table 2

Preclinical studies on the effects of YKS on PD-like symptoms in animal models of neurological disorders.

Symptoms	Species	Inducer	Extracts/components	Dose/route/regimen	Major finding	Histological & biochemical evaluation	Reference
Sleep	Male ddY mice (4 weeks old and 20–25g)	Social isolation for 9–12 weeks	YKS	300 mg/kg, p.o., 60 min prior to testing	Pentobarbital (50 mg/kg, i.p)-induced sleeping time ↑	Sleep inducing effect involving the – benzodiazepine receptor complex, but not 5- receptors	[22]
	Male ddY mice (4–6 weeks old and 19–32 g)		YKS	300 mg/kg, p.o.	Skin temperature ↓		[23]
Depression and anxiety	Male ICR mice; (25–30 g)	Restraint stress for 14 days	YKS	1000 mg/kg, p.o.		Inhibition of decreased excitatory amino acid transporter 2 expression in the PFC and hippocampus	[24]
Anxiety	ICR male mice (6 weeks old)	Placed on elevated open-platform	YKSCH	800 mg/kg, p.o.	Duration of freezing in EPM ↓	Anxiolytic effects via a selective inhibitor of serotonin reuptake	[25]
	F344/N aged; rats; (24 months old)	Aging	YKS	3% (w/w) food pellets for 3 months	Time and frequency; in the open arm of the EPM ↑; the number of excrements during locomotor activity measurement ↓	Improved concentrations of serotonin and dopamine in the PFC using microdialysis and NH3 in plasma	[26]
	Male Wistar/ST rats (10-13 weeks old)	Electric foot shock (aversive stressor)	YKS	1000 mg/kg, p.o., for 14 or 16 day	Freezing behavior ↓ in the CFC test; time spent in open arms ↑ in EPM test; unchanged locomotion	Anxiolytic effects via 5- receptors in memory-dependent fear induced by aversive stress; plasma corticosterone (-) after CFC stress in rats that had experienced footshock stress	[27]
	Male ddY mice (4 weeks old)	Social isolation stress for 6 weeks	YKS	1% and 3% (w/w) food pellets for 6 weeks	Rearing behavior ↓	Anxiolytic effect mediated with 5- receptor	[28]
	Male Wistar rats (250–300 g)	Cerebrovascular ischemia by the four-vessel occlusion method	YKS	100, 300, or 1000 mg/kg, p.o., for 14 days	The time in the dark box in the light/dark test and in the enclosed arm in EPM ↓; the proportion of counts in the outer area in OF test ↓; unchanged locomotion in the open-field	Antagonistic effect on wet-dog shakes induced by 5-agonist, DOI (5 mg/kg)	[29]
	Male ICR mice	CFC; consisting of inescapable foot-shocks	Co-treatment SSRI (fluvoxamine) +YKS	Fluvoxamine (5–20 mg/kg, i.p.) and YKS (0.3 and 1 g/kg, p.o.) for 6 days	Freezing behavior characterized as anxiety behavior ↓ in CFC	Decreased 5-, but not 5- receptor expression in the PFC	[30]
	F344/N male rats (10-13 weeks old)	Restraint stress for 1 h	YKS	100 or 300 mg/kg, p.o., for 1 h (single) or for 2 weeks (repeated)	Anxiety-related behavior in repeated administration ↓; unchanged locomotion by OF and EPM test	Decreased stress-induced c-Fos expression in the medial PFC and the basolateral and medial amygdaloid nuclei; serum corticosterone levels (-)	[31]
Hallucination	Male ddY mice (4 weeks old)	Isolation stress for 6 weeks; DOI, 2.5 mg/kg (i.p.)	YKS	1% and 3% (w/w) food pellets for 6 weeks or oral	DOI-induced head-twitch response ↓	Down regulation of 5- receptor density in the PFC	[32]
	Male ddY mice ( 4 weeks old and 20–25 g)	DOI, 5 mg/kg, i.p.	YKS	300 mg/kg, p.o., for 14 days repeated treatment	DOI-induced head twitch response ↓	Decreased expression of 5- receptors in the prefrontal cortex	[33]
Aggressiveness	Male Wistar rats (7 weeks old)	Social isolation for 11-13; weeks	YKS	100, 300 mg/kg, p.o.	Aggressive behavior ↓ using aggression test		[34]
	Male ddY mice (5 weeks old)	Methamphetamine			Methamphetamine-induced; hyperlocomotion ↓	Inhibition of hyperlocomotion via dopaminergic signaling
	Male ddY mice (6 weeks old)	Injection of Aβ into the lateral ventricle of the brain	YKS	0.5 or 1.0 g/kg for 3 weeks	Aggressive; behaviors including tail rattling, chase, and attack ↓		[35]
	Male Wistar rats (6 weeks old)	Injection of L-Glutamic acid into the right NBM	YKSCH	1.0 g/10 ml/g for 7 days	Aggressive behavior in resident-intruder tests ↓	Mediated by 5- receptor stimulation	[36]
	Male Wistar rats (7 weeks old)	Injection of PCA	YKS	0.5 or 1.0 g/kg single or chronic (2 weeks) after PCA injection	Aggressive behavior ↓	Agonistic effect on 5- receptors as buspirone (5- agonist) and chronic treatment with YKS inhibited aggressive behavior in PCA-injected rats	[37]
	Male ddY mice (3 weeks old)	Isolated zinc-deficient diet for 2 weeks	YKS	Drinking water containing YKS 300 mg/kg	Aggressive behavior in resident-intruder test ↓	Suppression of glutamatergic neuron activity; MK-801 (NMDA receptor antagonist) attenuated aggressive behavior in zinc-deficient mice	[38]
	Male ddY mice (3 weeks old)	Zinc-deficient diet for 2 weeks	YKS	Drinking water containing YKS 300 mg/kg	Aggressive behavior in resident-intruder test ↓	Lower serum glucocorticoid levels and ameliorated increased glutamate and GABA concentrations in brains of zinc-deficient mice	[39]
	Male ddY mice (3 weeks old) and male Wistar rats (3; weeks old)	Zinc-deficient diet for 2 weeks	YKSCH	Drinking water containing YKSCH 300 mg/kg; for 2 weeks	Aggressive behavior in resident-intruder test ↓	Attenuation of excess exocytosis at mossy fiber boutons induced with 60 mM KCl in hippocampus and intracellular Ca^2+ level by GA (100–500 μM) or GM (100 μM)	[40]
Cognition	Tg2576 mouse (5-15 months old)	AD	YKS	Powdered diets containing 0.5 and 1.0% YKS for 10 months	Learning disturbance in the Morris water-maze test ↓; time spent in the open arms in EPM test ↑; hyperactivity in OF test ↓	No inhibition of histological deposition or amounts of Aβ observed in Tg(+) mice	[41]
	Male Wistar rats (300–350 g)	Repeated cerebral ischemia	YKS and Angelica root	1000 mg/kg, p.o. for 7 days	Correct choice in 8 RAM task ↑	Upregulated the release of ACh; prevented 4-VO-induced hippocampal apoptosis	[42]
	Male Wistar; rats (230–270 g)	Four-vessel transient cerebral ischemia and Injection of Aβ into intracerebroventricularly	YKS	100, 300, or 1000 mg/kg, p.o. for 2 weeks	Correct choices ↑ and error choices ↓ in the 8 RAM task	Increase of high K^+-evoked potentiation of ACh release and expression of dynamin 1 in the hippocampus and leading to improved synaptic function	[43]
	OBX male ddY mice (9 weeks old)	AD	YKS	375–750 mg/kg, p.o.	Memory deficits in modified Y-maze test and novel object recognition test ↓; long term memory impairment in fear conditioning test (-)	Reversed OBX-induced down-regulation of ChAT and muscarinic M1 receptor expression without affecting muscarinic M3 receptor expression or AChE activity	[44]
	Naive male F344/N rats (24 months old)	Aging	YKS	3% (w/w) food pellets for 3 months	Accuracy in the delayed alternation ↑ (working memory); accuracy in reversal discrimination tasks ↑; (reversal learning)	Increase of dopaminergic signaling through D1 receptors in the PFC as the effect of YKS was reduced by intracranial infusion of a dopamine D1 receptor antagonist	[45]
	Male Wistar rats (3 weeks old and 35-45g)	Thiamine-deficient diet	YKS	Drinking water containing YKS 0.5, 1.0 g/kg	Memory disturbance; in step-through passive-avoidance test ↓	Inhibition of neuronal and astroglial cell degeneration in the brainstem, hippocampus, and cortex; inhibition of extracellular glutamate rise in the ventral posterior medial thalamus	[46]
	Male homozygous (j/j) Gunn rats; (7 weeks old)	Gunn rat, animal model of schizophrenia	YKS	Drinking water containing YKS 1 g/kg	Location index in object-location test ↑	Suppression of microglial activation; and promotion of neurogenesis in the hippocampus	[47]
Motor	Male Mongolian gerbils (60–80 g)	Cerebral ischemia by occlusion of bilateral common carotid arteries for 5 min	YKS	300 mg/kg, p. o. for 30 days	Ischemia-induced locomotor hyperactivity ↓; errors recorded in the 8-RAM task ↓	Decreased number of activated microglia in the CA1 based on Iba1 immunohistochemistry; amelioration of ischemia-induced oxidative DNA damage via 8-OHdG assay	[48]
Pain	Male SD rats (250-300g)	Chronic constriction injury	YKS	0.3, 1.0 g/kg, p.o.	Mechanical allodynia in the von Frey filament test ↓; cold allodynia in acetone test ↓	Inhibition of cerebrospinal fluid dialysate levels of glutamate; DL-threo-beta-hydroxyaspartate and dihydrokainate as glutamate transporter inhibitor reduced the antiallodynic effects of YKS	[49]
	Male ICR mice (5 weeks old)	Partial sciatic nerve ligation	YKS	1 g/kg, p.o.	Mechanical allodynia in the von Frey filaments test ↓	Inhibition of IL-6 mRNA expression in astrocytes and/or microglia in the spinal cord	[50]
Tardive dyskinesia	Male Wistar rats (5; weeks old)	Injection of haloperidol decanoate-into thigh muscle	YKS	0.1, 0.5 g/kg, p. o. for 3 weeks	Vacuous chewing movement ↓	Inhibition of increased striatal glutamate and GLT-1 mRNA levels in haloperidol-treated rats	[51]

DOI=1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, CFC=contextual fear conditioning, EPM=elevated plus-maze, OF=open-field, PFC=prefrontal cortex, Ach=acetylcholine, RI=repeated ischemia, ChAT=choline acetyltransferase, AchE=acetylcholinesterase, RAM=radial arm maze, YKSCH=Yokukansankachimpihange, PCA=para-chloroamphetamine, AD=Alzheimer’s disease, Aβ=amyloid β, GA=18β-glycyrrhetinic acid, GM=geissoschizine methyl ether, and 4-Vo=4-vessel occlusion.