Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway--do androgens matter?

Activation of poly (ADP-ribose) polymerases (PARP) contributes to ischemic damage by causing neuronal nicotinamide adenine dinucleotide (NAD(+)) depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. We observed smaller damage following focal cerebral ischemia (MCAO) in male PARP-1 knockout mice compared to wild type (WT) as well as decreased damage in male mice treated with the PARP inhibitor PJ34. Protection from ischemic damage provided by PJ-34 in WT mice is lost after removal of testicular androgens (CAST) and rescued by androgen replacement. CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicate that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.

[Clinical and diagnostic characteristics of T1 root syndrome]. / Klinische und diagnostische Charakteristika des Wurzelsyndroms Th1.

BACKGROUND: Among radicular lesions, those affecting the T1 root are rare. Together with the similarity of symptoms to C8 syndrome, which is more common, this makes the diagnosis of T1 radiculopathy complicated. The clinical and diagnostic specifics of T1 syndrome are shown here based on three cases. MATERIALS AND RESULTS: We report on three patients with T1 syndrome. Clinical diagnostics (clinical investigation, electrophysiology, MRI) showed in two cases lateral intraforaminal disc herniae at the T1-2 level, and the third patient had metastasis of a cervix carcinoma being responsible for the radiculopathy. In all cases surgery was performed. The patients with disc herniae were immediately pain-free after surgery; in the third patient the neurological symptoms and pain clearly improved. CONCLUSIONS: These three cases show that by thorough analysis of clinical symptoms and functional (electrophysiology) and morphological (MRI) diagnostics, T1 radiculopathy can be differentiated from C8 lesions. All of the patients benefited from decompressive surgery.

Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-kappaB transcriptional activity.

Acute and chronic neurodegeneration, for example, following brain injury or Alzheimer's disease, is characterized by programmed death of neuronal cells. The present study addresses the role and interaction of p53- and NF-kappaB-dependent mechanisms in delayed neurodegeneration following traumatic brain injury (TBI). After experimental TBI in mice p53 rapidly accumulated in the injured brain tissue and translocated to the nucleus of damaged neurons, whereas NF-kappaB transcriptional activity simultaneously declined. Post-traumatic neurodegeneration correlated with the increase in p53 levels and was significantly reduced by the selective p53 inhibitor pifithrin-alpha (PFT). Strikingly, this protective effect was observed even when PFT treatment was delayed up to 6 h after trauma. Inhibition of p53 activity resulted in the concomitant increase in NF-kappaB transcriptional activity and upregulation of NF-kappaB-target proteins, for example X-chromosomal-linked inhibitor of apoptosis (XIAP). It is interesting to note that inhibition of XIAP abolished the neuroprotective effects of PFT in cultured neurons exposed to camptothecin, glutamate, or oxygen glucose deprivation. In conclusion, delayed neuronal cell death after brain trauma is mediated by p53-dependent mechanisms that involve inhibition of NF-kappaB transcriptional activity. Hence, p53 inhibition provides a promising approach for the treatment of acute brain injury, since it blocks apoptotic pathways and concomitantly triggers survival signaling with a therapeutic window relevant for clinical applications.

Mechanism of progesterone neuroprotection of rat cerebellar Purkinje cells following oxygen-glucose deprivation.

The survival of rat Purkinje cell (PCs) cerebellar cultures was used to test the hypothesis that progesterone is protective against oxygen-glucose deprivation through potentiation of GABA(A) receptor activity. Electrophysiological recordings confirm that PCs develop robust excitatory and inhibitory synapses in culture. Exposure of cultured PCs to increasing concentrations of progesterone during oxygen-glucose deprivation revealed a concentration-dependent protection by progesterone, with significant protection observed at physiological concentrations, as low as 10 nm. The concurrent application of the GABA(A) receptor antagonist picrotoxin (100 microm) completely abolished the neuroprotection afforded by progesterone, indicating that progesterone is neuroprotective through activation of GABA(A) receptors. Progesterone potentiates GABA(A) receptor activity indirectly through its metabolites, such as allopregnanolone (ALLO). Therefore, ALLO was applied to PC cultures and was observed to produce significant protection at all concentrations tested, from 10 to 1000 nm. Finally, the inhibition of progesterone metabolism with finasteride abolished the protection afforded by progesterone without having any effect on the neuroprotection caused by ALLO. These data indicate that progesterone protects cerebellar PCs at physiological concentrations through a GABA-active metabolite.