Restoration of Akt activity by the bisperoxovanadium compound bpV(pic) attenuates hippocampal apoptosis in experimental neonatal pneumococcal meningitis

Abstract

Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-triphosphate (PIP 3 ) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP 3 and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.

Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury

“…PTEN antagonizes phosphatidylinositol-3-kinase (PI3K) activity, limiting survival signaling through Akt and its effectors such as mammalian target of rapamycin (mTOR) (Nave et al, 1999), bcl-2-associated death promoter (BAD) (Datta et al, 1997), and glycogen synthase kinase 3β (GSK3β) (Cross et al, 1995). Neuroprotective and reparative effects of bpVs have been widely demonstrated in neurological disease and injury models (Mao et al, 2013; Song et al, 2010; Sury et al, 2011; Yang et al, 2007; Zhang et al, 2007; Zhao et al, 2013) including SCI (Nakashima et al, 2008; Walker et al, 2012). …”

Targeting PTEN using small molecule inhibitors

“…Enhancing the PI3K-Akt pathway through PTEN inhibition improved self-renewal of human foreskin [30] bpV(pic) 20µg/100 g Wistar rats Prevents ischemic brain injury by activating the mTOR signaling pathway [31] bpV(pic) 2mg/1000g Wistar rats Attenuation of hippocampal apoptosis [32] bpV(pic) 10 -90 nM SH-SY5Y cells Reduction of okadaic acidinduced tau phosphorylation [33] …”

PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries

“…In addition, downregulating PTEN’s function or expression promotes axon regeneration and neuroprotection following CNS trauma (Park et al, 2008; Liu et al, 2010b; Zhang et al, 2007; Walker et al, 2012a). Beneficial effects of its inhibition are usually attributed to disinhibition of PI3K and downstream signaling through Akt (Zhang et al, 2007; Sury et al, 2011; Walker et al, 2012a) and the mammalian target of rapamycin (mTOR) (Shi et al, 2009; Shi et al, 2011; Zhong and Bowen, 2011) (Fig. 1).…”

“…Pharmacological enzymatic disruption of signaling molecules like PTEN provides a much more convenient and less extreme method of assessing an enzymes’ activity. For example, bisperoxovanadium compounds, also known as bpVs, specifically inhibit PTEN signaling, and have been used for promotion of neuroprotection in many CNS injury studies (Yang et al, 2007; Zhang et al, 2007; Nakashima et al, 2008; Sury et al, 2011; Walker et al, 2012a). …”