Table 2.

Preclinical or clinical evidence on different PDE inhibitors—other than ibudilast—for neurodegenerative diseases, their PDE targets and main mechanisms of action.

PDE Inhibitor	PDE Target	Clinical Trials	Main Effects and Mechanism of Action in Neurodegenerative Diseases	Reference
Alzheimer’s Disease
Rolipram	PDE4	-	Inhibition of Aβ-mediated cognitive decline, via the regulation of neuroinflammatory and apoptotic responses in rats through cAMP/CREB signaling.	[55]
Zatomilast	PDE4	Phase 1 clinical trials (NCT02648672, NCT02840279, NCT03030105); Phase 2 clinical trial (NCT03817684).	Improvement of memory, prevention of the loss of dendrites and spine density, inhibition of amyloid-beta-induced reduction of CREB, BDNF and NGF in the hippocampus of mice models of AD.	[57]
Cilostazol	PDE3	Randomized, placebo-controlled phase 4 clinical trial (NCT01409564).	Prevention of amyloid-beta-induced oxidative stress and memory impairment.	[58]
		-	Prevention of APOE-mediated amyloid-beta aggregation in mice.	[59]
		-	Induction of proteasome-mediated proteolysis, suppression of tauopathy and attenuation of cognitive impairment.	[60]
		-	Regulation of autophagy by upregulating SIRT1, and enhancement of amyloid-beta clearance and cell viability.	[61]
Parkinson’s disease
Rolipram	PDE4	-	Inhibition of MPTP-induced dopamine loss in the striatum of mice, and prevention of dopaminergic neuronal loss in the SN.	[68]
FCPR16	PDE4	-	Prevention of the MPP+-induced reduction of oxidative stress and the potential of the mitochondrial membrane.	[69]
Zaprinast	PDE6, 5, 11 and 9	-	Prevention of cAMP and cGMP dysregulation in levodopa-induced dyskinesias in 6-OHDA-treated rat models of PD.	[70]
Multiple Sclerosis
Rolipram	PDE4	Phase 2 clinical trial (NCT00011375).	Prevention of the clinical signs of demyelination in EAE rat models, reduction of TNF-α production in MBP-specific T cells.	[89]
		-	Reduction of TNF-α levels, prevention of clinical signs of MS and neuroimaging abnormalities on MRI in marmoset models of EAE.	[90]