Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology.

Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa-/-) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa-/- mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa-/- spinal cord. Third, many signal transduction pathways in the Gaa-/- cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were "synaptic plasticity pathways" including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system.

Delta-opioid receptor activation prolongs respiratory motor output during oxygen-glucose deprivation in neonatal rat spinal cord in vitro.

Delta opioid receptor (DOR) activation protects the adult mammalian brain during oxygen-glucose deprivation (OGD), but it is not known whether neonatal spinal motor circuits are also protected. Also, it is unclear whether the timing of spinal DOR activation relative to spinal OGD is important for neuroprotection. Thus, a split-bath in vitro neonatal rat brainstem/spinal cord preparation was used to record spontaneous respiratory motor output from cervical (C4-C5) and thoracic (T5-T6) ventral spinal roots while exposing only the spinal cord to OGD solution (0 mM glucose, bubbled with 95% N(2)/5% CO(2)) or DOR agonist drugs (DADLE, DPDPE). Spinal OGD solution application caused respiratory motor output frequency and amplitude to decrease until all activity was abolished (i.e. end-point times) after 25.9±1.4 min (cervical) and 25.2±1.4 min (thoracic). Spinal DOR activation via DPDPE (1.0 µM) prior-to and during spinal OGD increased cervical and thoracic end-point times to 35-48 min. Spinal DADLE or DPDPE (1.0 µM) application 15 min following spinal OGD onset increased cervical and thoracic end-point times to 36-45 min. Brief spinal DPDPE (1.0 µM) application for 10 min at 25 min before spinal OGD onset increased cervical and thoracic end-point times to 41-46 min. Overall, the selective DOR agonist, DPDPE, was more effective at increasing end-point times than DADLE. Naltrindole (DOR antagonist; 10 µM) pretreatment blocked DPDPE-dependent increase in end-point times, suggesting that DOR activation was required. Spinal naloxone (1.0 µM) application before and during spinal OGD also increased end-point times to 31-33 min, but end-point times were not altered by Mu opioid receptor (MOR) activation or DOR activation/MOR blockade, indicating that there are complex interactions between OGD and opioid signaling pathways. These data suggest DOR activation before, during, and after spinal OGD protects central motor networks and may provide neuroprotection during unpredictable perinatal ischemic events.