Table 2 Adenosine homeostasis-related proteins as drug targets in neurodegenerative diseases
Disease | Target | Effect | Model | References |
|---|---|---|---|---|
AD | ENT1 | Enhanced spatial memory Enhanced synaptic transmission | Pharmacological inhibitor (J4) of ENT1 in APP/PS1 mouse model | [144] |
Enhanced spatial memory Reduced AMPK activity Reduced ADA, CD39 and CD73 levels | Pharmacological inhibitor (J4) of ENT1 in Thy-Tau22 mouse model | [46] | ||
CD73 | Enhanced memory and synaptic function | Genetic knockout of CD73 in a β-amyloid (Aβ1-42)-based mouse model of early AD | [93] | |
AMPK | Enhanced long-term potentiation (LTP) | Pharmacological inhibitor (compound C) of AMPK in APP/PS1 mouse model | [162] | |
Enhanced spatial memory Reduced tau acetylation level | AAV-mediated AMPK overexpression in APP/PS1 mouse model | [232] | ||
Enhanced spatial memory | AAV-mediated AMPK overexpression in STZ-treated mouse model | [232] | ||
Enhanced spatial memory | Pharmacological activator of AMPK (metformin) in APP/PS1 mouse model | [236] | ||
Enhanced learning and memory Enhanced cognitive function | Genetic repression of AMPKα1 in Tg19959 mouse model | [262] | ||
Enhanced learning and memory Enhanced cognitive function | Genetic repression of AMPKα1 in APP/PS1 mouse model | [262] | ||
PD | ADA | ADA inhibition alleviated neuroinflammation, dopamine deficit, dopaminergic neuronal loss, and motor impairment | MPTP-induced mouse model | [114] |
ADA inhibition strengthened the protective effects of A2AR antagonist | MPTP-induced mouse model | [114] | ||
ADA application prevented 6-OHDA-induced neurotoxicity | 6-OHDA-treated differentiated SH-SY5Y cells | [38] | ||
CD73 | Microglial-mediated inflammation, dopaminergic neuronal loss, and motor deficits were partially attenuated in CD73 KO mice | MPTP-induced mouse model | [175] | |
CD73 blockade prevented 6-OHDA-induced neurotoxicity | 6-OHDA-treated differentiated SH-SY5Y cells | [38] | ||
Central administration of a CD73 inhibitor attenuated dopamine loss, dopaminergic neuronal death, motor dysfunction, and memory decline | 6-OHDA-induced rat model | [38] | ||
AMPK | AMPK activation protected against α-synuclein accumulation, mitochondrial dysfunction, production of ROS, and neuronal death | α-Synuclein-, 6-OHDA-, and MPTP-induced models | ||
HD | ENT1 | Enhanced survival | Genetic knockout of ENT1 in R6/2 mouse model | [127] |
Enhanced survival Improved motor function | Pharmacological inhibitor (JMF1907) of ENT1 in R6/2 mouse model | [127] | ||
AMPK | Enhanced survival | Pharmacological activator of AMPK (metformin) in R6/2 mouse model | [163] | |
Reversed early cortical network dysfunction | Pharmacological activator of AMPK (metformin) in Hdh150Q mouse model | [12] | ||
Improved motor and neuropsychiatric function | Pharmacological activator of AMPK (metformin) in zQ175 mouse model | [205] | ||
Improved cognitive function | Pharmacological activator of AMPK (metformin) in HD patients | [107] | ||
ALS | ENT1 | Reduced AMPK activity Improved motor function | Pharmacological inhibitor (JMF1907) of ENT1 in TDP-43 mouse model | [155] |
AMPK | Increased differentiation rate | Pharmacological activator of AMPK (Resveratrol) in ALS patients-derived BM-MSCs | [256] | |
Delayed disease progression | Pharmacological activator of AMPK (Latrepirdine) in SOD1 (G93A) mouse model | [58] | ||
Improved behavioral phenotypes Enhanced motor neuron survival | Pharmacological activator of AMPK (metformin) in C9orf72 ALS/FTD BAC mouse model | [263] | ||
Reduced AMPK activity Enhanced motor neuron survival Delayed disease progression Extended the lifespan | A high-fat diet in SOD1 (G93A) mouse model | [257] | ||
Epilepsy | ENT1 | Intrahippocampal injection of an ENT1 inhibitor ameliorated seizure severity and prolonged the onset latency | Pilocarpine-induced rat model | [248] |
Intraperitoneal injection of ENT1 inhibitors exhibited anti-seizure activities | Maximal electroshock-, pentylenetetrazol-, or kindling-induced mouse models | [111] | ||
ADK | An ADK inhibitor suppresses seizure activity | Kainic acid-induced mouse model | [96] | |
Genetic reduction of ADK reduced seizure activity and neuronal injury | Kainic acid-induced mouse model | [152] | ||
AMPK | AMPK activation by metformin decreased mTOR phosphorylation and seizure activity | Pilocarpine-induced rat model | [172] | |
AMPK activation by metformin reduced the mortality and the duration of seizures | Pentylenetetrazol and kainic acid-induced mouse models | [252] | ||
Sleep disturbances | ENT1 | Decreased sleep duration Decreased extracellular adenosine | Genetic knockout of ENT1 mouse model | [132] |
ADK | Decreased sleep duration | Transgenic overexpression of ADK mouse model | [189] | |
CD73 | Decreased sleep duration | Genetic knockout of CD73 mouse model | [260] | |
AMPK | Decreased sleep depth | Pharmacological inhibitor (compound C) of AMPK in wild-type mouse model | [53] | |
Enhanced sleep depth | Pharmacological activator (AICAR) of AMPK in wild-type mouse model | [53] |