Mn texaphyrins

Administration of Mn Porphyrin and Mn Texaphyrin at Symptom Onset Extends Survival of ALS Mice... 

Onset Adndnistration of Mn Texaphyrin Extends Survival of G93A Mice... 

Mn Texaphyrin (2.5 m g/day following 5.0 mg/kg loading dose on day one) was administered via intraperitoneal injection beginning on the first day ofsymptom onset in each mouse. Left panel shows classic Kaplan-Meier survival curves and right panel shows the survival interval (time from onset to death) in each group. 

Decreasing the frequency of Mn texaphyrin dosing to less than once per day significantly reduced the survival benefit. Aside from this, very little is known about die dose-response or dosing frequency required for efficacy with the Mn texaphyrin. However, it is clear that diis conqiound produced a survival effect that ranks among the best ever reported—particularly for an onset administration paradi n— and that further studies are warranted. 

Cohort studies with Mn texaphyrin have not yet been completed. However, preliminary HPLC analysis of end-stage Mn texaphyrin-treated mice indicate lower levels of nitrotyrosine in the spinal cord relative to untreated controls (Dr. Darren Magda, unpublished data 2003). Lowered nitrotyrosine levels, udiether assessed quantitatively by HPLC or qualihitively by immunhistochemistry, are totally consistent with peroxynitrite scavenging by Mn porphyrin and Mn texaphyrin. However, indirect mechanisms involving activation of cellular defense and repair mechanisms may also be playing an inportant role. 

Both the semi-planar, four coordinate Mn porphyrin and the non-planar five coordinate Mn texaphyrin are stable Mn confounds which are capable of using cellular reductants to catalytically deconq>ose peroxynitrite. There is no indication that the in vivo effects of either confound are related to release of fi ee Mn and the lack of therapeutic effect from administration of manganese chloride to G93A mice has been reported previously (44). In addition, we have seen no therapeutic effect of zinc or cobalt analogs of FeTCPP, suggesting fiiat a redox active metal is required such results are consistent with catalytic antioxidant properties. 

The cadmium(II) complex corresponding to 9 (M = Cd n = 2) was the first texaphyrin made [6], This aromatic expanded porphyrin was found to differ substantially from various porphyrin complexes and it was noted that its spectral and photophysical properties were such that it might prove useful as a PDT agent. However, it was also appreciated that the poor aqueous solubility and inherent toxicity of this particular metal complex would likely preclude its use in vivo [29-31], Nonetheless, the coordination chemistry of texaphyrins such as 9 was soon generalized to allow for the coordination of late first row transition metal (Mn(II), Co(II), Ni(II), Zn (II), Fe(III)) and trivalent lanthanide cations [26], This, in turn, opened up several possibilities for rational drag development. For instance, the Mn(II) texaphyrin complex was found to act as a peroxynitrite decomposition catalyst [32] and is being studied currently for possible use in treating amyotrophic lateral sclerosis. This work, which is outside the scope of this review, has recently been summarized by Crow [33],... 

The scavenging and quenching mechanism described above would apply to the redox cycle of Mn(III)/Mn(IV) porphyrin or Mn(II)/Mn(III) texaphyrin. The environment of the Mn in the texaphyrin stabilizes the +2 state and does not allow the Mn to become oxidized to +4 (32). Under in vitro conditions, the Mn in the porphyrin exists in the +3 state and does cycle to +4 upon reaction with peroxynitrite (27-31). However, in the presence of reductants (and at much lower oxygen tensions), as would exist intraceUularly, the porphyrin Mn would likely exist in the +2 state a redox cycle from +2 to +4 would allow it to con5)letely reduce peroxynitrite and thereby totally quench its oxidative reactivity (31,30). 

---