PARP (Poly ADP-ribose polymerase) inhibitors represent a promising therapeutic approach for neurodegenerative diseases by modulating DNA repair pathways, preserving NAD+ metabolism, and reducing neuroinflammation[1].
PARP enzymes play a critical role in single-strand DNA repair through base excision repair (BER)[2]. In neurodegenerative diseases, chronic oxidative stress and mitochondrial dysfunction lead to increased DNA damage. PARP inhibition preserves cellular energy by preventing excessive NAD+ depletion during DNA repair activation[3].
Overactivation of PARP1 leads to catastrophic NAD+ depletion, impairing cellular energy metabolism and contributing to neuronal death[4]. PARP inhibitors protect NAD+ pools by preventing excessive poly(ADP-ribosyl)ation, thereby maintaining sirtuin activity and mitochondrial function[5].
PARP activation contributes to neuroinflammation through NF-κB pathway activation and pro-inflammatory cytokine release[6]. PARP inhibitors reduce microglial activation and inflammatory responses in models of Alzheimer's and Parkinson's disease[7].
PARP inhibition offers particular promise for CBS and PSP through several mechanisms:
DNA Repair in Tauopathies
Neuroinflammation Modulation
Mitochondrial Protection
Preclinical Rationale
PARP inhibition represents a novel approach for FTD subtypes:
TDP-43 Pathology
Genomic Instability
C9orf72 Expansion
PARP offers multiple therapeutic targets in HD:
DNA Repair Deficiency
NAD+ Depletion
Striatal Vulnerability
Therapeutic Potential
Common adverse effects include:
CNS-penetrant PARP inhibitors are being developed to reduce peripheral toxicity while maintaining neuroprotective effects[21].
PARP inhibitors face significant challenges crossing the blood-brain barrier:
| Property | Impact on BBB Penetration |
|---|---|
| Molecular weight | >500 Da reduces CNS penetration |
| Polar surface area | >90 Ų limits brain uptake |
| P-gp efflux | Active efflux reduces brain exposure |
| Drug | MW (Da) | P-gp substrate | CNS penetration |
|---|---|---|---|
| Olaparib | 434 | Yes | Limited |
| Niraparib | 320 | Yes | Moderate |
| Rucaparib | 323 | Yes | Limited |
| Veliparib | 277 | No | Good |
| Talazoparib | 380 | Yes | Limited |
Structural Modifications
Formulation Approaches
Novel CNS-Penetrant PARP Inhibitors
Combining PARP inhibitors with NAD+ precursors (e.g., nicotinamide riboside, nicotinamide mononucleotide) may provide synergistic neuroprotection by preserving both NAD+ consumption and enhancing NAD+ biosynthesis[22].
PARP inhibition may complement mitochondrial-targeted therapies in diseases with dual DNA damage and mitochondrial dysfunction[23].
PARP inhibitors reduce neuroinflammation through:
Combination with NLRP3 inhibitors or CSF1R inhibitors may provide additive benefits.
For 4R tauopathies (CBS/PSP):
PARP inhibition may enhance AAV-mediated gene therapy:
| Trial | Drug | Condition | Phase | Status |
|---|---|---|---|---|
| NCT04824538 | Olaparib | Parkinson's Disease | Phase 2 | Recruiting |
| NCT05160606 | Talazoparib | ALS | Phase 1 | Completed |
| NCT05318764 | Veliparib | Stroke | Phase 2 | Completed |
Total Program Cost: $38-63M over 60 months
Martinez-Banaclocha M. PARP-1 activity in chronic neurodegeneration: therapeutic target. J Neurochem. 2020. ↩︎
Besset V, et al. DNA repair in Alzheimer's disease. J Alzheimers Dis. 2019. ↩︎
Kauppinen TM, et al. Poly(ADP-ribose) polymerase-1 and neurodegeneration. Nat Rev Neurosci. 2011. ↩︎
Minhas PS, et al. NAD+ repletion improves mitochondrial and stem cell function. Nature. 2021. ↩︎
Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015. ↩︎
Chiu CY, et al. Neuroinflammation in neurodegenerative diseases: Role of PARP. Front Aging Neurosci. 2020. ↩︎
Wang X, et al. PARP inhibition attenuates neuroinflammation. Neurobiol Aging. 2020. ↩︎
Zhou J, et al. PARP1 promotes tau pathology. Nat Neurosci. 2020. ↩︎
Strosznajder JB, et al. PARP inhibition in Alzheimer's disease. Neurochem Res. 2005. ↩︎
Wu PJ, et al. PARP improves DNA repair and cognition in AD models. Cell Rep. 2022. ↩︎
Kim TW, et al. PARP-1 in dopaminergic neuron death. Mol Neurobiol. 2018. ↩︎
Mandir AS, et al. PARP inhibition protects against MPTP-induced parkinsonism. Proc Natl Acad Sci USA. 1999. ↩︎
Liu H, et al. PARP and alpha-synuclein aggregation. Mol Neurodegener. 2021. ↩︎
McGurk L, et al. PARP activation in ALS. Nat Neurosci. 2018. ↩︎
Song L, et al. PARP inhibition extends survival in ALS models. Brain. 2022. ↩︎
Harlan BA, et al. NAD+ and PARP combination therapy. Trends Neurosci. 2021. ↩︎
AstraZeneca. Olaparib clinical development. 2024. ↩︎
Clovis Oncology. Rucaparib pipeline. 2024. ↩︎
GSK. Niraparib research program. 2024. ↩︎
AbbVie. Veliparib clinical trials. 2024. ↩︎
Ferraris DV, et al. CNS-penetrant PARP inhibitors. J Med Chem. 2020. ↩︎
Xie Y, et al. NAD+ precursor and PARP inhibitor combination. Nat Commun. 2021. ↩︎
Morovicz AP, et al. Targeting PARP and mitochondria in neurodegeneration. Pharmacol Res. 2022. ↩︎