Disease relevance of AG-127

• Protein tyrosine kinase inhibitors of the tyrphostin AG 126 family protect mice against LPS-induced lethal toxicity [1].
• Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death [2].
• These results demonstrate that inhibition of AG 126-sensitive tyrosine kinase pathways may provide new approaches for preventing excessive inflammation and reducing the increases in blood flow and intracranial pressure in the acute phase of bacterial meningitis [3].
• Tyrphostin AG 126 inhibits development of postoperative ileus induced by surgical manipulation of murine colon [4].
• The tyrosine kinase inhibitor tyrphostin AG 126 reduced the development of colitis in the rat [5].

High impact information on AG-127

• Furthermore, this inhibitory effect correlated with the potency of AG 126 to block LPS-induced tyrosine phosphorylation of a p42MAPK protein substrate in the murine macrophage [1].
• Of 10 substances tested, only the protein tyrosine kinase inhibitor tyrphostin AG 126 discriminated significantly between PG and LPS: TNF-alpha release induced by PG, but not by LPS, was dose-dependently suppressed [6].
• These data indicate that increased K(+) efflux via P2X(7) nucleotide receptor stimulation activates AG-126- and bromoenol lactone-sensitive signaling pathways in murine macrophages that result in stably maintained signals for caspase-1 regulation in cell-free assays [7].
• Inhibition of extracellular signal-regulated kinase (ERK)-1/2 (with PD-98059 or AG-126) also reduced VEGF-induced hyperpermeability but did not block VEGF-induced vasodilation [8].
• Furthermore, tyrphostin AG 126 pretreatment significantly inhibited activation of multifactorial transcription factor NF-kappaB, which could form the basis for reduction in proinflammatory mediator expression [4].

Anatomical context of AG-127

• Tyrosine kinase blockers from the AG 126/AG-556 tyrphostin family are shown to inhibit the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in primary rat astrocytes cultures [9].

Associations of AG-127 with other chemical compounds

• Furthermore, treatment of rats with tyrphostin AG 126 significantly reduced the production of peroxynitrite and of pro-inflammatory cytokines TNF-alpha and IL-1beta [10].

Gene context of AG-127

• The degree of staining for nitrotyrosine, PAR, iNOS, and COX-2 were markedly reduced in tissue sections obtained from zymosan-treated rats which had received tyrphostin AG 126 [10].
• Tyrphostins AG-126 and AG-556 were previously shown to reduce TNF-alpha production and its end-organ cytotoxicity, thus proving beneficial in animal models of septic shock and experimental autoimmune encephalomyelitis [11].
• Using a rodent model of colonic postoperative ileus, we demonstrate that a single bolus injection of the PTK inhibitor tyrphostin AG 126 (15 mg/kg sc) before surgery significantly attenuates the surgically induced impairment of colonic contractility both in vivo and in vitro [4].
• Similarly, AG-556 administered for an additional 10 days after myosin immunization (when signs of inflammation are already present) attenuated the progression of myocarditis, though AG-126 did not [11].

References