Table 3.
Pre-clinical studies of PARP-1 inhibitors in neurodegenerative diseases. Table displaying examples of in vitro and in vivo models of brain disorders in which PARP-1 inhibitors have shown efficacy.
| Disease/Unhealthy Condition | In Vivo Pre-Clinical Model | Effects of PARP-1 Inhibitor | In Vitro Pre-Clinical Model | Effect of PARP-1 Inhibitor | References |
|---|---|---|---|---|---|
| Parkinson’s disease | MTPT mouse model | Benzamide show protective effects against the catecholamine depletions induced by MPTP in cortex and striatum and prevents NAD+ and ATP depletion. | Neurons purified from a Parkinson’s disease mouse model injected with preformed α-synuclein fibrils | Rucaparib or Veliparib reduces α-synuclein phosphorylation and aggregation, spreading and neurotoxicity | [97,102,103] |
| Alzheimer’s disease | 3 × Tg-AD mouse model | Nicotinamide reduces levels of phosphorylated species of tau and β-amyloid in the hippocampus and cerebral cortex and restores cognitive functions. | Rat pheochromocytoma (PC12) cells treated with 1 μM Aβ 1–42 oligomers Neuroblastoma cells (SH-SY5Y) treated with Aβ25–35 fragment |
PJ-34 enhances transcription of antioxidant genes and regulation of mitochondria function. MC2050 diminishes NF-κB activation, ROS production, and pro-apoptotic proteins. |
[101,104,105,106] |
| Stroke | Mouse model of middle cerebral artery occlusion (MCAO) Mouse model of transient middle cerebral artery occlusion MCAO rat model injected with thrombin |
PJ34 alleviates post-stroke neuro-inflammation and neurological deficits and suppresses microglial activation. Olaparib reduces infarct size, immunoglobulin G extravasation, and ameliorates neurological deficits. HYDAMTIQ reduces neurological impairment by up to 40% INO-1001 reduces infarct volume by 86%, prevents AIF migration to the nucleus |
Cultured human neurons exposed to oxygen–glucose deprivation (OGD) | Olaparib reduces OGD-induced neuronal cell death. | [106,107,108,109] |
| Multiple sclerosis | A primary demyelination mouse model, induced by a copper chelator cuprizone in weanling mice, results in multi-focal demyelination and loss of oligodendrocytes in the corpus callosum and superior cerebellar peduncle EAE mouse model EAE mouse model |
4-hydroxyquinazoline (4HQ) protects against cuprizone-induced demyelination in the brain, prevents weight loss, decreases AIF-mediated cell death. PJ34 suppresses the development of clinical signs of EAE, reduces CNS Inflammation in the spinal cord, and limits BBB disruption. INH2BP delays onset and reduces severity of EAE reducing the expression of pro-inflammatory molecules and immune cells infiltration. |
Primary mouse neurons exposed to chondroitin sulfate proteoglycans (CSPGs) | PJ34, 4HQ, or 3AB promote neurite outgrowth | [50,91,92,110] |
| Traumatic brain injury and Disrupted blood brain barrier | Controlled cortical impact mouse model Controlled cortical impact rat model |
PJ-34 administration improves motor functions, reduces AIF release from mitochondria and neuronal loss in cortex and hippocampus. INO-1001 administration suppresses microglia activation |
Primary brain microvascular endothelial cells (BMVEC) | 5-aminoisoquinoline or Olaparib increases BBB integrity, down-regulate production of pro-inflammatory molecules and decreases human monocyte adhesion, migration through BBB. | [49,107,111] |