Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat

Abstract

Impaired cerebellar development of premature infants and the associated impairment of cerebellar functions in cognitive development could be crucial factors for neurodevelopmental disorders. Anesthetic- and hyperoxia-induced neurotoxicity of the immature brain can lead to learning and behavioral disorders. Dexmedetomidine (DEX), which is associated with neuroprotective properties, is increasingly being studied for off-label use in the NICU. For this purpose, six-day-old Wistar rats (P6) were exposed to hyperoxia (80% O2) or normoxia (21% O2) for 24 h after DEX (5 µg/kg, i.p.) or vehicle (0.9% NaCl) application. An initial detection in the immature rat cerebellum was performed after the termination of hyperoxia at P7 and then after recovery in room air at P9, P11, and P14. Hyperoxia reduced the proportion of Calb1+-Purkinje cells and affected the dendrite length at P7 and/or P9/P11. Proliferating Pax6+-granule progenitors remained reduced after hyperoxia and until P14. The expression of neurotrophins and neuronal transcription factors/markers of proliferation, migration, and survival were also reduced by oxidative stress in different manners. DEX demonstrated protective effects on hyperoxia-injured Purkinje cells, and DEX without hyperoxia modulated neuronal transcription in the short term without any effects at the cellular level. DEX protects hyperoxia-damaged Purkinje cells and appears to differentially affect cerebral granular cell neurogenesis following oxidative stress.

Cardioprotective Effects of Dexmedetomidine in an Oxidative-Stress In Vitro Model of Neonatal Rat Cardiomyocytes

“…Shown in H9c2 cells under OGD/R injury as well as in CoCl 2 -induced injury to mimic hypoxia [ 71 ], both Hif1α and autophagy-related mediators are induced [ 72 ]. Compared to previous studies, DEX demonstrated a protective effect on cardiomyocytes by inhibiting ROS-induced apoptosis [ 41 ], an antioxidant effect on the developing rodent brain [ 73 ], as well as known neuroprotective mechanisms in general [ 74 , 75 ]. Li et al [ 76 ] demonstrated the protection of H9c2 cells against CoCl 2 -induced damage using the antioxidant naringin, a natural bioflavonoid, by enhancing autophagic flux via activation of the Hif1α/BNIP3 pathway.…”

Dexmedetomidine Protects Cerebellar Neurons against Hyperoxia-Induced Oxidative Stress and Apoptosis in the Juvenile Rat

“…Experimental studies showed neuroprotective effects, clinically complemented by a reduced need for additional sedation and by the reduced use of opioids and benzodiazepines without suppressing respiration. Antioxidative mechanisms in the sense of a reduction of oxidative stress and subsequent anti-neurodegenerative and anti-inflammatory effects have already been demonstrated [31][32][33], as well as neuroprotection by DEX in the toxic oxygen model of our group [34][35][36].…”

“…Two days before the planned date of birth, the rats were kept in individual cages. As previously described [34][35][36]84,85], newborn pups remain with a lactating mother for the entire duration of the experiment. The dams were allowed to birth naturally and were disturbed for the first time to randomize the pups on postnatal day (P)4.…”