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P2‐399: Active immune intervention for prionoses in deer
Author(s) -
Wisniewski Thomas,
Mathiason Candace,
Wong Kinlung,
HayesKlug Jeanette,
Nalls Amy,
Anderson Kelly,
Estevez Veronica,
Yim Lucia,
Brown David,
Chabalgoity Jose Alejandro,
Hoover Edward,
Goni Fernando
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1109
Subject(s) - saliva , chronic wasting disease , titer , immune system , biology , feces , immunology , antibody , antibody titer , horizontal transmission , virology , tonsil , vaccination , immunoglobulin a , microbiology and biotechnology , immunoglobulin g , medicine , virus , disease , prion protein , biochemistry , scrapie
micromolar range. We previously reported that the drug showed neuroprotective potential against amyloid toxicity in mice. In particular, ANAVEX2-73 attenuated the oxidative stress, caspases induction, cellular loss and learning and memory deficits observed in mice one week after the icv injection of an oligomeric preparation of amyloid beta-(25-35) peptide (Abeta 25-35) (Villard et al., J Psychopharmacol 2011). More recently, we reported that ANAVEX2-73 blocked the Abeta 25-35 -induced P-Akt decrease and P-GSK-3beta increase, indicating activation of the PI3K neuroprotective pathway (Lahmy et al., Soc Neurosci Abstr 2011). As a result, ANAVEX2-73 attenuated, in the dose-range tested, the hyperphosphorylation of Tau on physiological epitopes (AT-8 antibody clone) and on pathological epitopes (AT-100 clone). ANAVEX273 also decreased the Abeta 25-35 -induced endogenous Abeta 1-42 seeding. The drug may thus act as a disease-modifying agent not only protecting brain cells from toxicity but also contributing to decrease Tau pathology and amyloid load. Methods:We here analyzed the impact of administration schedule and combination with donepezil on the efficacy of the drug. Results: ANAVEX2-73 (0.1, 0.3 mg/kg ip), administered once a day between day -7 and day -1 before Abeta 25-35 (day 0), blocked the Abeta 25-35 -induced memory deficits (spontaneous alternation in the Y maze and passive avoidance response) and lipid peroxidation in the hippocampus 7 days after Abeta 25-35. ANAVEX2-73 (0.3 mg/kg ip) was also effective when it was administered once a day between day 7 and day 13 after Abeta 25-35 (on day 0), on memory deficits and lipid peroxidation increase measured 14 days after Abeta 25-35. In combination with donepezil (0.25, 0.5 mg/kg ip), the effects appeared synergistic, since the combination of the lowest non-effective doses (0.25 donepezil + 0.1 ANAVEX2-73) led to a significant protection on all parameters examined. Combination studies with memantine are in progress. Conclusions: These results showed a good preventing and restorating efficacy for the compound in the Abeta 25-35 model in mice and showed a preserved efficacy in combination with the reference acetylcholinesterase inhibitor.