Table 2.

Cholinergic-based treatments which have demonstrated beneficial effects in pre-clinical HD studies. Strength of evidence criteria was based on proper study design, number of subjects improved, level of improvement, lack of side effects and replication by others

Treatment	Beneficial effect(s)	Animal model	Number of animals studied	Reference(s)	Strength of	Comments
					evidence
Donepezil	improves cognitive function	R6/2 transgenic mice	First study: n = 73 (across 4 groups); second study: n = 55 (across 4 groups)	[66]	8/10	Appropriate study design, appropriate mouse model, high number of mice used, results replicated in individual studies.
Galantamine	reduces neurological deficits, striatal lesions and apoptosis	3-nitropropionic acid rat model	n = 46 (across 5 groups)	[69]	4/10	Appropriate study design although some groups with low numbers of mice, animal model used not ideal.
VU0467154	improves motor and synaptic function	YAC128 transgenic mice	Motor function: n = 41 (across 4 groups); synaptic function: n = 43 (across 4 groups)	[85]	6/10	Appropriate study design, highly valid animal model used.
Physostigmine	increases hippocampal cell proliferation	Wistar rats	n = 30 (across 5 groups)	[79]	4/10	Animal model not HD-specific, relatively low numbers of animals.
Oxotremorine	increases hippocampal cell proliferation, spatial working memory and reverses deficits in hippocampal neurogenesis	Wistar rats	n = 30 (across 5 groups)	[79]	5/10	Multiple beneficial effects but animal model not HD-specific.
NGF	improves motor and cognitive function; increases cholinergic cell survival, expression of ChAT, VAChT and trkA markers, hippocampal neurogenesis; reduces excitotoxicity and cholinergic cell atrophy	R6/1 mice, YAC128 mice, Sprague-Dawley rats, Wistar rats	R6/1 mice: n = 48 (across 4 groups); YAC128 mice: n = 64 (across 4 groups); SD rats study 1: n = 29 (across 4 groups); SD rats study 2: n = 27 (across 4 groups); SD rats study 3: n = 37 (across 4 groups); SD rats study 4: n = 18 (across 3 groups)	[48, 87, 88, 90–95]	9/10	Appropriate study designs, valid animal models used, numerous beneficial effects reported, beneficial effects found by multiple research groups.
			Wistar rats: n = 8 (across 2 groups)