Nestorone (segesterone acetate) effects on neuroregeneration.

Nestorone® (segesterone acetate) is a progestin with a chemical structure closely related to progesterone with high affinity and selectivity for the progesterone receptor without significant interaction with other steroid receptors. It has been developed for female and male contraception and is FDA-approved in a first long-acting contraceptive vaginal system for female contraception. Its safety has been extensively demonstrated in both preclinical and clinical studies for contraceptive indications. Nestorone was found to display neuroprotective and neuroregenerative activity in animal models of various central nervous system diseases, including multiple sclerosis, stroke, and amyotrophic lateral sclerosis. Reviewed herein are neuroprotective and myelin- regenerating properties of Nestorone in various animal models and its translational potential as a therapeutic agent for debilitating neurological diseases for which limited therapeutic options are available (Table 1).

Spectroscopic Investigation on the Primary Photoreaction of Bathy Phytochrome Agp2-Pr of Agrobacterium fabrum: Isomerization in a pH-dependent H-bond Network.

Bathy phytochrome Agp2 from Agrobacterium fabrum exhibits an unusually low pKa =7.6 in the Pr state in contrast to a pKa >11 in the Pfr state, indicating a pH-dependent charge distribution and H-bond network in the Pr chromophore binding pocket around neutral pH. Here, we report on ultrafast UV/Vis absorption spectroscopy of the primary Pr photoisomerization of Agp2 at pH 6 and pH 9 and upon H2 O/D2 O buffer exchange. The triexponential Pr kinetics slows down at increased pH and pronounced pH-dependent kinetic isotope effects are observed. The results on the Pr photoreaction suggest: 1) component-wise hindered dynamics on the chromophore excited-state potential energy surface at high pH and 2) proton translocation processes either via single-proton transfer or via significant reorganization of H-bond networks. Both effects reflect the interplay between the pH-dependent charge distribution in the Pr chromophore binding pocket on the one hand and chromophore excitation and its Z→E isomerization on the other hand.

Ultrafast deactivation of bilirubin: dark intermediates and two-photon isomerization.

Bilirubin is a neurotoxic product responsible for neonatal jaundice, which is generally treated by phototherapy. The photoreaction involves ultrafast internal conversion via an elusive intermediate and Z-E isomerization with minor yield (less than 3% in solution). The structure of the intermediate remains unclear. Here, the combination of UV-vis and mid-IR ultrafast transient absorption spectroscopy reports a comprehensive picture of the mechanism and provides essential structural information about the intermediate species. Thus, spectral dynamics during the earliest ps unveils a wavepacket travelling from the Franck-Condon region to the crossing point with a dark state. The latter shows a tighter molecular skeleton than the ground state and decays with 15 ps time constant. Remarkably, the relative contribution of a non-decaying component increases linearly with pump energy, suggesting that Z-E isomerization could also be triggered by two-photon excitation. Implications for the photochemistry of protein-bound open tetrapyrroles are discussed.

Femtosecond dynamics in the lactim tautomer of phycocyanobilin: a long-wavelength absorbing model compound for the phytochrome chromophore.

Transient UV/Vis absorption spectroscopy is used to study the primary dynamics of the ring-A methyl imino ether of phycocyanobilin (PCB-AIE), which was shown to mimic the far-red absorbance of the Pfr chromophore in phytochromes (R. Micura, K. Grubmayr, Bioorg. Med. Chem. Lett.- 1994, 4, 2517-2522). After excitation at 615 nm, the excited electronic state is found to decay with τ1 =0.4 ps followed by electronic ground-state relaxation with τ2 =1.2 and τ3 =6.7 ps. Compared with phycocyanobilin (PCB), the initial kinetics of PCB-AIE is much faster. Thus, the lactim structure of PCB-AIE seems to be a suitable model that could not only explain the bathochromic shift in the ground-state absorption but also the short reaction of the Pfr as compared to the Pr chromophore in phytochrome. In addition, the equivalence of ring-A and ring-D lactim tautomers with respect to a red-shifted absorbance relative to the lactam tautomers is demonstrated by semiempirical calculations.

Unusual spectral properties of bacteriophytochrome Agp2 result from a deprotonation of the chromophore in the red-absorbing form Pr.

Phytochromes are widely distributed photoreceptors with a bilin chromophore that undergo a typical reversible photoconversion between the two spectrally different forms, Pr and Pfr. The phytochrome Agp2 from Agrobacterium tumefaciens belongs to the group of bathy phytochromes that have a Pfr ground state as a result of the Pr to Pfr dark conversion. Agp2 has untypical spectral properties in the Pr form reminiscent of a deprotonated chromophore as confirmed by resonance Raman spectroscopy. UV/visible absorption spectroscopy showed that the pKa is >11 in the Pfr form and ∼7.6 in the Pr form. Unlike other phytochromes, photoconversion thus results in a pKa shift of more than 3 units. The Pr/Pfr ratio after saturating irradiation with monochromatic light is strongly pH-dependent. This is partially due to a back-reaction of the deprotonated Pr chromophore at pH 9 after photoexcitation as found by flash photolysis. The chromophore protonation and dark conversion were affected by domain swapping and site-directed mutagenesis. A replacement of the PAS or GAF domain by the respective domain of the prototypical phytochrome Agp1 resulted in a protonated Pr chromophore; the GAF domain replacement afforded an inversion of the dark conversion. A reversion was also obtained with the triple mutant N12S/Q190L/H248Q, whereas each single point mutant is characterized by decelerated Pr to Pfr dark conversion.