Table 1.

Therapeutic potential of P2X4 modulators, antagonists or allosteric modulators in CNS pathologies.

Pathology	Model	Therapeutic Benefit	Ref.
Neuropathic and inflammatory pain	Peripheral nerve or spinal cord injury in mice	Antisense oligonucleotide to P2X4 alleviates neuropathic pain	[17]
		P2X4−/− mice lack mechanical hyperalgesia and have reduced inflammatory pain	[40,51]
		Neuropathic pain was alleviated in the present of P2X4 antagonists such as paroxetine, duloxetine, NP-1815-PX	[64,65]
Spinal cord and peripheral nerve injury	Spinal cord injury in mice	P2X4R−/− mice showed impaired inflammasome signaling and improved functional outcome	[45]
	Sciatic nerve crush in mice	Overexpression of P2X4R promoted motor and sensory functional recovery	[50]
Epilepsy	Kainate induced status epilepticus in mice	P2X4−/− mice showed ameliorated microglia response and reduced neuronal death	[66]
Ischemia	Middle cerebral artery occlusion (MCAO) (60 min) in mice	P2X4−/− mice showed reduced infarct volume	[67]
	MCAO in mice	P2X4R antagonists did not affect MCAO-mediated infarct formation	[68]
	Neonatal hypoxia in mice	TNP-ATP antagonist reduced hypomyelination and cognitive decline	[69]
Multiple sclerosis	Experimental autoimmune encephalomyelitis	Ivermectin ameliorate clinical signs	[24]
	Lysolecithin (LPC) model in organotypic slices	Ivermectin potentiates remyelination after in LPC-induced demyelination	[24]
Parkinson’s disease	6-hydroxydopamine model of DA depletion	P2X4R KO mice exhibited an attenuated levodopa (L-DOPA)-induced motor behavior, whereas ivermectin enhanced this behavior	[70]
Alzheimer’s disease	Amyloid β (Aβ) exposure in vitro	Overexpression of P2X4Rs in neurons enhanced Aβ toxicity while silencing of P2X4Rs decreased neuronal death	[71]
	Conditional knock-in mice (P2X4mCherryIN) mimicking the pathological increase of surface P2X4R	Impairment of memory processing and altered synaptic plasticity in the hippocampus	[59]
Psychiatric disorders	P2X4R KO mice	P2X4 KO mice showed altered prepulse inhibition and reductions in social interactions	[70,72,73]
	Alcohol use disorders models in mice	Ivermectin and other avermectins reduces EtOH intake and preference	[74,75]
	Anxiety	Increases surface expression of P2X4 at excitatory synapses alleviates anxiety	[59]