Whether erythropoietin can be a neuroprotective agent against premature brain injury: cellular mechanisms and clinical efficacy

: Preterm infants are at high risk of brain injury. With more understanding of the preterm brain injury's pathogenesis, neuroscientists are looking for more effective methods to prevent and treat it, among which erythropoietin (Epo) is considered as a prime candidate. This review tries to clarify the possible mechanisms of Epo in preterm neuroprotection and summarize updated evidence considering Epo as a pharmacological neuroprotective strategy in animal models and clinical trials. To date, various animal models have validated that Epo is an anti-apoptotic, anti-inflammatory, anti-oxidant, anti-excitotoxic, neurogenetic, erythropoietic, angiogenetic, and neurotrophic agent, thus preventing preterm brain injury. However, although the scientific rationale and preclinical data for Epo's neuroprotective effect are promising, when translated to bedside, the results vary in different studies, especially in its long-term efficacy. Based on existing evidence, it is still too early to recommend Epo as the standard treatment for preterm brain injury.

Multifaceted Brain Age Measures Reveal Premature Brain Aging and Associations with Clinical Manifestations in Schizophrenia

Schizophrenia is a mental disorder with extensive alterations of cerebral gray matter (GM) and white matter (WM) and is known to have advanced brain aging. However, how the structural alterations contribute to brain aging and how brain aging is related to clinical manifestations remain unclear. Here, we estimated the bias-free multifaceted brain age measures in patients with schizophrenia (N=147) using structural and diffusion magnetic resonance imaging data. We calculated feature importance to estimate regional contributions to advanced brain aging in schizophrenia. Furthermore, regression analyses were conducted to test the associations of brain age with illness duration, onset age, symptom severity, and intelligence quotient. The patients with schizophrenia manifested significantly old-appearing brain age (P<.001) in both GM and WM compared with the healthy norm. The GM and WM structures contributing to the advanced brain aging were mostly located in the frontal and temporal lobes. Among the features, the GM volume and mean diffusivity of WM were most sensitive to the neuropathological changes in schizophrenia. The WM brain age index was associated with a negative symptom score (P=.006), and the WM and multimodal brain age indices demonstrated negative associations with the intelligence quotient (P=.037; P=.040, respectively). Moreover, brain age exhibited associations with the onset age (P=.006) but no associations with the illness duration, which may support the early-hit non-progression hypothesis. In conclusion, our study reveals the structural underpinnings of premature brain aging in schizophrenia and its clinical significance. The brain age measures might be a potentially informative biomarker for stratification and prognostication of patients with schizophrenia.

Comparison of Effects of Metformin, Phenformin, and Inhibitors of Mitochondrial Complex I on Mitochondrial Permeability Transition and Ischemic Brain Injury

Damage to cerebral mitochondria, particularly opening of mitochondrial permeability transition pore (MPTP), is a key mechanism of ischemic brain injury, therefore, modulation of MPTP may be a potential target for a neuroprotective strategy in ischemic brain pathologies. The aim of this study was to investigate whether biguanides—metformin and phenformin as well as other inhibitors of Complex I of the mitochondrial electron transfer system may protect against ischemia-induced cell death in brain slice cultures by suppressing MPTP, and whether the effects of these inhibitors depend on the age of animals. Experiments were performed on brain slice cultures prepared from 5–7-day (premature) and 2–3-month old (adult) rat brains. In premature brain slice cultures, simulated ischemia (hypoxia plus deoxyglucose) induced necrosis whereas in adult rat brain slice cultures necrosis was induced by hypoxia alone and was suppressed by deoxyglucose. Phenformin prevented necrosis induced by simulated ischemia in premature and hypoxia-induced—in adult brain slices, whereas metformin was protective in adult brain slices cultures. In premature brain slices, necrosis was also prevented by Complex I inhibitors rotenone and amobarbital and by MPTP inhibitor cyclosporine A. The latter two inhibitors were protective in adult brain slices as well. Short-term exposure of cultured neurons to phenformin, metformin and rotenone prevented ionomycin-induced MPTP opening in intact cells. The data suggest that, depending on the age, phenformin and metformin may protect the brain against ischemic damage possibly by suppressing MPTP via inhibition of mitochondrial Complex I.