Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity

NAPVSIPQ (NAP), an active fragment of the glial-derived activity-dependent neuroprotective protein, is protective at femtomolar concentrations against a wide array of neural insults and prevents ethanol-induced fetal wastage and growth retardation in mice. NAP also antagonizes ethanol inhibition of L1-mediated cell adhesion (ethanol antagonism). We performed an Ala scanning substitution of NAP to determine the role of ethanol antagonism and neuroprotection in NAP prevention of ethanol embryotoxicity. The Ser-Ile-Pro region of NAP was crucial for both ethanol antagonism and protection of cortical neurons from tetrodotoxin toxicity (neuroprotection). Ala replacement of either Ser-5 or Pro-7 (P7A-NAP) abolished NAP neuroprotection but minimally changed the efficacy of NAP ethanol antagonism. In contrast, Ala replacement of Ile-6 (I6A-NAP) caused a decrease in potency (>2 logarithmic orders) with only a small reduction (<10%) in the efficacy of NAP neuroprotection but markedly reduced the efficacy (50%) and the potency (5 logarithmic orders) of NAP ethanol antagonism. Ethanol significantly reduced the number of paired somites in mouse whole-embryo culture; this effect was prevented significantly by 100 pM NAP or by 100 pM P7A-NAP, but not by 100 pM I6A-NAP. The structure–activity relation for NAP prevention of ethanol embryotoxicity was similar to that for NAP ethanol antagonism and different from that for NAP neuroprotection. These findings support the hypothesis that NAP antagonism of ethanol inhibition of L1 adhesion plays a central role in NAP prevention of ethanol embryotoxicity and highlight the potential importance of ethanol effects on L1 in the pathophysiology of fetal alcohol syndrome

A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice

ABSTRACT Brain injury induces disruption of the blood-brain barrier, edema, and release of autodestructive factors that produce delayed neuronal damage. NAPSVIPQ (NAP), a femtomolaracting peptide, is shown to be neuroprotective in a mouse model of closed head injury. NAP injection after injury reduced mortality and facilitated neurobehavioral recovery (P Ͻ 0.005). Edema was reduced by 70% in the NAP-treated mice (P Ͻ 0.01). Furthermore, in vivo magnetic resonance imaging demonstrated significant brain-tissue recovery in the NAP-treated animals. NAP treatment decreased tumor necrosis factor-␣ levels in the injured brain and was shown to protect pheochromocytoma (PC12 cells) against tumor necrosis factor-␣-induced toxicity. Thus, NAP provides significant amelioration from the complex array of injuries elicited by head trauma

A peptide derived from Activity-Dependent Neuroprotective Protein (ADNP) ameliorates injury response in closed head injury in mice

Brain injury induces disruption of the blood-brain barrier, edema, and release of autodestructive factors that produce delayed neuronal damage. NAPSVIPQ (NAP), a femtomolar-acting peptide, is shown to be neuroprotective in a mouse model of closed head injury. NAP injection after injury reduced mortality and facilitated neurobehavioral recovery (P < 0.005). Edema was reduced by 70% in the NAP-treated mice (P < 0.01). Furthermore, in vivo magnetic resonance imaging demonstrated significant brain-tissue recovery in the NAP-treated animals. NAP treatment decreased tumor necrosis factor-α levels in the injured brain and was shown to protect pheochromocytoma (PC12 cells) against tumor necrosis factor-α-induced toxicity. Thus, NAP provides significant amelioration from the complex array of injuries elicited by head trauma

A peptide derived from Activity-Dependent Neuroprotective Protein (ADNP) ameliorates injury response in closed head injury in mice

Brain injury induces disruption of the blood-brain barrier, edema, and release of autodestructive factors that produce delayed neuronal damage. NAPSVIPQ (NAP), a femtomolar-acting peptide, is shown to be neuroprotective in a mouse model of closed head injury. NAP injection after injury reduced mortality and facilitated neurobehavioral recovery (P < 0.005). Edema was reduced by 70% in the NAP-treated mice (P < 0.01). Furthermore, in vivo magnetic resonance imaging demonstrated significant brain-tissue recovery in the NAP-treated animals. NAP treatment decreased tumor necrosis factor-α levels in the injured brain and was shown to protect pheochromocytoma (PC12 cells) against tumor necrosis factor-α-induced toxicity. Thus, NAP provides significant amelioration from the complex array of injuries elicited by head trauma