Acute Low Dose Naltrexone Increases ß-Endorphin and Promotes Neuronal Recovery Following Hypoxia-Ischemic Stroke in Type-2 Diabetic Mice.

Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia-ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release ß-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of ß-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10 week old male db/db and db/ + mice, collected tissue at 24 and 72 h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1 mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48 h post HI, and collected brain tissue and blood at 72 h. Acute LDN treatment increased ß-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN.

Opioid growth factor receptor: Anatomical distribution and receptor colocalization in neurons of the adult mouse brain.

The opioid growth factor (OGF) is an endogenous peptide that binds to the nuclear-associated receptor (OGFr), and plays a significant role in the proliferation of developing, renewing, and healing tissues. The receptor is widely expressed in a variety of organs, however its distribution in the brain remains unknown. In this study, we investigated the distribution of OGFr in different brain regions of male heterozygous (-/+ Lepr db/J), non -diabetic mice and determined the localization of the receptor in three major brain cell types, astrocytes, microglia, and neurons. Immunofluorescence imaging revealed that the highest number of OGFr was in hippocampal CA3 subregion followed by primary motor cortex, hippocampal CA2, thalamus, caudate and hypothalamus in a descending order. Double immunostaining revealed receptor colocalization with neurons and little or no colocalization in microglia and astrocytes. The highest percentage of OGFr positive neurons was identified in the CA3. Hippocampal CA3 neurons play an important role in memory processing, learning and behavior, and motor cortex neurons are important for muscle movement. However, the significance of the OGFr receptor in these brain regions and its relevance in diseased conditions are not known. Our findings provide a basis for understanding the cellular target and interaction of the OGF- OGFr pathway in neurodegenerative diseases such as Alzheimer's, Parkinson's, and stroke where hippocampus and cortex have an important role. This foundational data may also be useful in drug discovery to modulate OGFr by opioid receptor antagonist in various CNS diseases.