Table 2.

Pharmacological and genetic inhibition of DNMTs in primary neuron and mouse models of HD and other neurodegenerative conditions.

Neuronal insults and disease models	Methods targeting DNMTs	Beneficial effects	Reference
Primary neuron cultures
Mutant HTT-expressing primary cortical and striatal neurons	Decitabine, FdCyd; DNMT RNAi	Treatment with decitabine, FdCyd, or shRNAs targeting DNMT3A and DNMT1 attenuated mutant HTT (exon 1)-induced transcriptional changes and neurodegeneration in mouse primary cortical and striatal neuron systems. Decitabine treatment reduced the levels of mutant HTT aggregates in primary cortical neurons.	Pan et al. (2016)
Oxidative stress in primary cerebellar granule neurons	Decitabine	Hydrogen peroxide-induced neuronal death and reduction of Klotho protein levels were rescued by decitabine treament in mouse primary cerebellar granule neurons.	Xin et al. (2015)
Retinal photoreceptors from a mouse model of retinitis pigmentosa	Decitabine	Decitabine treatment reduced photoreceptor cell death in organotypic retinal explant cultures from a mouse model of retinitis pigmentosa.	Farinelli et al. (2014)
Mouse models in vivo
HD	FdCyd	Striatal genes downregulated in R6/2 HD mouse brain, including Drd2, Adora2a, Ppp1r1b, and Rosd2, were restored by ICV infusion of FdCdy by osmotic pump.	Pan et al. (2016)
SBMA	RG108	ICV infusion of RG108 by osmotic pump improved motor function and survival of AR-97Q SBMA mice. RG108 treatment suppressed spinal motor neuron atrophy in AR-97Q mice.	Kondo et al. (2019)
Scitatic nerve avlusion	RG108	Inhibition of DNMTs with RG108 blocked the increase in 5mC present in the cytoplasm and the nucleus and the apoptosis of motor neurons induced by sciatic nerve avulsion in adult mice.	Chestnut et al. (2011)
Ischemic brain injury	Decitabine; Dnmt1 heterozygous KO	ICV pre-administration of decitabine in WT mice reduced ischemic brain damage after mild focal ischemia (MCAo/reperfusion). Mutant mice heterozygous for a Dnmt1 gene deletion were resistant to mild ischemic damage.	Endres et al. (2000)
	Conditional Dnmt1 heterozygous KO (CamKIIa-Cre)	Reduced levels of DNMT1, but not its complete deletion, in postmitotic neurons of the postnatal brain showed smaller infarcts following MCAo/reperfusion compared to control WT.	Endres et al. (2001)

ICV, intracerebroventricular; decitabine (5-aza-2′-deoxycytidine) and FdCyd (5-fluoro-2′-deoxycytidine), nucleoside analog DNMT inhibitors; RG108, non-nucleoside DNMT inhibitor; HD, Huntington’s disease; SBMA, spinal and bulbar muscular atrophy; AR, androgen receptor; MCAo, middle cerebral artery occlusion; KO, knockout.