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Figure 3

Figure 3. From: Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer's Disease.

Optimal allopregnanolone therapeutic regimen. Triple-transgenic Alzheimer’s disease (3xTgAD) mice were treated subcutaneously with allopregnanolone (APα; 10 mg/kg) once per month (1/month), once per week (4/month), or every other day (12/month) to determine extent of neurogenesis (depicted by red colored arrow) and pathology reduction capacity (depicted by black colored arrow) on double y-axes (Chen et al., 2011). The dosing frequency determined the therapeutic efficacy for both neurogenic and pathological endpoints. All three APα treatments were initiated when 3xTgAD mice reached 3 months of age. Upon completion of each treatment paradigm, BrdU+ labeled nuclei were counted to assess neurogenesis. Both the 1/month APα treatment and the 4/month APα treatment induced a significant increase in neurogenesis, with the latter regimen yielding the greater increase in neurogenesis. However, the 3/week/3 months (12/month) treatment induced a significant decrease in neurogenesis. Brain sections from 3xTgAD mice treated with APα or vehicle were immunostained. Aβ immunoreactivity was detected and indicated that the 1/week/6 months (4/month) APα treatment significantly decreased Aβ immunoreactivity. Efficacy of Aβ reduction in 4/month was comparable to the 12/month APα treatment whereas the 1/month APα treatment was ineffective at reducing Aβ immunoreactivity (Chen et al., 2011). From these dosing frequency studies, we conclude that the optimal treatment regimen for AD is to intervene as early as possible with once per week administration of APα to simultaneously promote neurogenesis and subsequent cell survival.

Ronald W. Irwin, et al. Front Endocrinol (Lausanne). 2011;2:117.
Figure 1

Figure 1. From: Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer's Disease.

Allopregnanolone (APα) mechanism of action promotes neurogenesis. (1) APα activates the GABA type A receptor to initiate the efflux of chloride ions (Cl) from neural progenitor and neural stem cells. (2) Extrusion of Cl from the intracellular compartment leads to membrane depolarization and activation of the voltage dependent L-type calcium channel. (3) The intracellular calcium (Ca++) rise activates Ca++dependent kinases that ultimately lead to regulation of gene expression and protein synthesis of cell cycle proteins. (4) Involving the transcription factor cyclic AMP response element binding protein (CREB) signaling pathway, APα up-regulates the expression of cell cycle genes that promote neural progenitor mitosis while simultaneously down regulating genes that repress cell division. (5) The mechanism of APα-induced neurogenesis takes advantage of the developmentally regulated direction of Cl flux to induce neurogenesis in those cells that are phenotypically competent to divide while not activating those mechanisms in mature neurons (Wang et al., 2005; Brinton and Wang, 2006). Adult hippocampal neural progenitor cells (BrdU+ cells immunolabeled green; NeuN+ cells are colored red; coronal section of mouse hippocampal dentate gyrus; scale bar = 50 μm) in the image above are shown as an illustrative example of neurogenesis within the mouse dentate gyrus subgranular zone (SGZ). Newly born granule cells proliferate and develop into neurons and glia along the border between the hilus and the granule cell layer. Migration (through the vertical space of the granule cell layer (GCL); arrows indicate sequence of temporal development) and integration of these cells occurs within the days and weeks following proliferation. Newly born neurons that survive will continue to mature and send axonal projections to form mossy fiber synapses in the CA3 subfield and dendrites to extend into the molecular cell layer (MCL) to receive glutamatergic afferents from the perforant pathway of the entorhinal cortex.

Ronald W. Irwin, et al. Front Endocrinol (Lausanne). 2011;2:117.
Figure 2

Figure 2. From: Neuroregenerative Mechanisms of Allopregnanolone in Alzheimer's Disease.

Cognitive efficacy of allopregnanolone (APα) prior to extraneuronal beta-amyloid plaque. Triple-transgenic Alzheimer’s disease (3xTgAD) mice were exposed to a single dose of APα. Data were plotted as percent change relative to age-matched vehicle control to assess the age-related differences in response to APα administered at 3-, 6-, 9-, or 12-months of age. Mice were treated with either APα (subcutaneous, 10 mg/kg) or vehicle and 1 h later with bromodeoxyuridine (BrdU) (intraperitoneal, 100 mg/kg). Learning and memory performances were measured by trace eyeblink conditioning, a hippocampal-dependent task. Mice were trained by pairing delivery of a tone (conditioned stimulus; CS, 250 ms, 2 kHz, 85 dB) as the conditioned stimulus followed by a 250-ms period of no stimuli, followed by a mild periorbital shock (unconditioned stimulus; US, 100 ms) to elicit an eyeblink response. Mice received two blocks of 30 trials per day (30–60 s intertrial intervals, 3–4 h interblock intervals). This behavioral paradigm is subthreshold for inducing neurogenesis (Wang et al., 2010; Singh et al., 2011). One week following a single dose of APα, mice were subjected to trace eyeblink conditioning, with 1 day of habituation and 5 days of paired training. Following paired training, mice were left undisturbed in their home cages for 9 days and subsequently were tested for memory. Following the final learning trial, BrdU+ cell survival/hippocampus was measured at the end of the study, 3-weeks following a single dose of APα and the thymidine analog DNA-synthesis marker BrdU. Bars represent percent change ± sem in response to a single exposure to APα compared to age-matched vehicle at 3-, 6-, 9-, 12-months of age in 3xTgAD mice (n ≥ 7; Wang et al., 2010; Singh et al., 2011). Within 3 weeks following a single exposure to APα, neurogenesis, maximal learning, and memory indicators were increased ∼100% relative to age-matched vehicle control in adult male 3xTgAD mice when administered at ages prior to overt AD pathology. The 3xTgAD mouse model displays age-associated decrements in endogenous neurogenic cell survival in the subgranular zone (SGZ) as compared with the non-transgenic mice in addition to age-associated increments in Aβ pathology burden (depicted supra to bar graph). At 12-months of age, intra- and extraneuronal Aβ 6E10 antibody staining is apparent and plaque structures are developed in subiculum (Wang et al., 2010; Singh et al., 2011). The therapeutic response to APα was specific to the transgenic AD phenotype, as the age-matched non-transgenic mice did not benefit from a single exposure to APα. Remarkably, a single exposure to APα increased neurogenesis and subsequent cell survival in aged non-transgenic mice when administered at 15-months of age (non-Tg data not in figure; Singh et al., 2011). At 12-months of age, the point when extraneuronal plaques are known to be present in this AD mouse model, a single exposure to APα was ineffective. At ages prior to extraneuronal Aβ plaques, APα significantly (P < 0.05) increased BrdU+ cell survival, maximal learning, and memory function relative to age-matched vehicle control.

Ronald W. Irwin, et al. Front Endocrinol (Lausanne). 2011;2:117.

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