The 5α-reductase inhibitor finasteride increases suicide-related aggressive behaviors and blocks clozapine-induced beneficial effects in an animal model of schizophrenia.

Death by suicide is 5 times higher among schizophrenia patients than in the general population. There is now compelling evidence suggesting that the pathophysiology of suicide in schizophrenia does not involve central serotonergic neurotransmission disturbances, as has been shown in other contexts. We recently developed and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation with polyI:C at gestational day 12 followed by post-weaning social isolation). In this THMS model, we have recently shown that the atypical antipsychotic clozapine normalized the prepulse inhibition (PPI) deficits as well suicide-related, impulsive aggressive and anxiety-like behaviors. While the mechanisms underlying the suicide-reducing benefits of clozapine in schizophrenic patients are not well understood, previous works have revealed that clozapine alters brain levels of neurosteroids, such as allopregnanolone. In the present study, we thus investigated the role of endogenous neurosteroids in clozapine action by evaluating whether the 5α-reductase inhibitor finasteride could overturn the ability of clozapine to reduce suicide-related behaviors. We found that clozapine significantly improved the PPI deficits in THMS mice, which could not be reversed by finasteride treatment. However, finasteride counteracted the ability of clozapine to decrease the exploratory behaviors in the open-field test. In the resident-intruder test, THMS mice showed exacerbated aggressiveness and impulsivity following finasteride alone. In this resident-intruder paradigm, clozapine alone effectively blocked the finasteride-enhanced effects on aggression and impulsivity. Altogether, these findings support the existence of a complex interaction between clozapine and neurosteroids in THMS mice. Further investigations are now required to clarify the details of the molecular mechanisms involved.

Neuroprotective effects of hypothermia in inflammatory-sensitized hypoxic-ischemic encephalopathy.

BACKGROUND: Despite the recent introduction of hypothermia as a mandatory standard of care, the incidence of neonatal encephalopathy in full-term newborns and its devastating neuro-behavioral outcomes continues to be a major individual, familial and social issue. Neonatal encephalopathy is mainly due to the compounding and interacting effects of hypoxia-ischemia and inflammation resulting from placental and other perinatal infections. It is unclear why hypothermia is effective in alleviating neonatal encephalopathy in some, but not all, full-term newborns. However, newborns exposed to inflammatory-sensitized hypoxia-ischemia seem to have less therapeutic benefit from hypothermia than those exposed to hypoxia-ischemia alone. OBJECTIVES: To clarify this uncertainty, we tested the efficacy of hypothermia in a double-hit model of neonatal encephalopathy induced by inflammatory-sensitized hypoxia-ischemia. METHODS: Using a rat preclinical model of endotoxin plus hypoxia-ischemia-induced neonatal encephalopathy of term newborns, we assessed the following in pups exposed (or not) to hypothermia: the extent of brain injuries and the expressions of molecules implicated in neural cell death, namely: pro-inflammatory cytokines, matrix metalloproteinase-9, antioxidant enzymes, as well as receptor-interacting protein-3. RESULTS: Hypothermia was neuroprotective on inflammatory-sensitized hypoxia-ischemia-induced penumbra, but not core, brain injuries. This beneficial effect was associated with a hypothermia-induced increase of antioxidant enzymes (superoxide dismutase-1, glutathione peroxidase-1), but was not associated with any variations of the other inflammatory mediators tested, namely: interleukin-1ß, interleukin-1 receptor antagonist, tumor necrosis factor-α and matrix metalloproteinase-9. CONCLUSION: Hypothermia is neuroprotective against inflammatory-sensitized hypoxia-ischemia possibly through a hypothermia-induced increase of antioxidant enzymes. This neuroprotective effect seems to be independent of the interleukin-1 system.