Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical outcomes in neurobehavioral tests mainly by modulating the inflammasome activation. These results suggest that Olaparib, a commercially available drug already in use as an anti-neoplastic compound, exerts a neuroprotective effect and could be a useful pharmaceutical agent for Huntington’s disease therapy.

Background and Purpose—Experimental evidence supports a major role of increased intracellular calcium [Ca²⁺]_ilevels in the induction of neuronal damage during cerebral ischemia. However, the source of Ca²⁺rise has not been fully elucidated. To clarify further the role and the origin of Ca²⁺in cerebral ischemia, we have studied the effects of various pharmacological agents in an in vitro model of oxygen (O₂)/glucose deprivation.Methods—Pyramidal cortical neurons were intracellularly recorded from a slice preparation. Electrophysiological recordings and microfluorometric measurements of [Ca²⁺]_iwere performed simultaneously in slices perfused with a glucose-free physiological medium equilibrated with a 95% N₂/5% CO₂gas mixture.Results—Eight to twelve minutes of O₂/glucose deprivation induced an initial membrane hyperpolarization, followed by a delayed, large but reversible membrane depolarization. The depolarization phase was accompanied by a transient increase in [Ca²⁺]_ilevels. When O₂/glucose deprivation exceeded 13 to 15 minutes, both membrane depolarization and [Ca²⁺]_irise became irreversible. The dihydropyridines nifedipine and nimodipine significantly reduced either the membrane depolarization or the [Ca²⁺]_ielevation. In contrast, tetrodotoxin had no effect on either of these parameters. Likewise, antagonists of ionotropic and group I and II metabotropic glutamate receptors failed to reduce the depolarization of the cell membrane and the [Ca²⁺]_iaccumulation. Finally, dantrolene, blocker of intracellular Ca²⁺release, did not reduce both electrical and [Ca²⁺]_ichanges caused by O₂/glucose depletion.Conclusions—This work supports a role of L-type Ca²⁺channels both in the electrical and ionic changes occurring during the early phases of O₂/glucose deprivation.

We have studied the electrophysiological effects of glucose deprivation on morphologically identified striatal neurons recorded from a corticostriatal slice preparation. The large majority of the recorded cells were spiny neurons and responded to aglycemia with a slow membrane depolarization coupled with a reduction of the input resistance. In voltage-clamp experiments aglycemia caused an inward current. This current was associated with a conductance increase and reversed at −40 mV. The aglycemia-induced membrane depolarization was not affected by tetrodotoxin (TTX) or 6-cyano-7-nitroquinoxaline-2,3-dione plus aminophosphonovalerate, antagonists acting respectively on AMPA and NMDA glutamate receptors. Also, the intracellular injection of bis(2-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid, a calcium (Ca²⁺) chelator, and low Ca²⁺/high Mg²⁺-containing solutions failed to reduce this phenomenon. Conversely, it was reduced by lowering external sodium (Na⁺) concentration.A minority of the recorded cells had the morphological characteristics of large aspiny interneurons and the electrophysiological properties of “long-lasting afterhyperpolarization (LA) cells.” These cells responded to aglycemia with a membrane hyperpolarization/outward current that was coupled with an increased conductance. This current was not altered by TTX, blockers of ATP-dependent potassium (K⁺) channels, and adenosine A1 receptor antagonists, whereas it was reduced by solutions containing low Ca²⁺/high Mg²⁺. This current reversed at −105 mV and was blocked by barium, suggesting the involvement of a K⁺conductance. We suggest that the opposite membrane responses of striatal neuronal subtypes to glucose deprivation might account for their differential neuronal vulnerability to aglycemia and ischemia.