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Table 2 Adenosine homeostasis-related proteins as drug targets in neurodegenerative diseases

From: Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on 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 [64, 103]
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]
  1. 6-OHDA, 6-hydroxydopamine; ADA, adenosine deaminase; ADK, adenosine kinase; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK, AMP-activated protein kinase; M-MSC, Bone marrow mesenchymal stem cells; ENT1, equilibrative nucleoside transporter 1; KO, knockout; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ROS, reactive oxygen species; STZ, Streptozotocin