A novel Aß-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice.

Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to ß-amyloid (Aß), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aß-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aß-fibrinogen interaction. RU-505 restored Aß-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aß-fibrinogen interaction show promise as therapy for treating AD.

Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats.

PURPOSE: Rapamycin (RAP) has certain antiepileptogenic features. However, it is unclear whether these effects can be explained by the anticonvulsant action of RAP, which has not been studied. To address this question, we tested potential anticonvulsant effects of RAP in immature and adult rats using different seizure models and treatment paradigms. In addition, we studied changes in the expression of neuropeptide Y (NPY) induced by RAP, which may serve as an indirect target of the RAP action. METHODS: A complex approach was adopted to evaluate the anticonvulsant potential of RAP: We used flurothyl-, pentylenetetrazole (PTZ)-, N-methyl-D-aspartate (NMDA)-, and kainic acid (KA)-induced seizures to test the effects of RAP using different pretreatment protocols in immature and adult rats. We also evaluated expression of NPY within the primary motor cortex, hippocampal CA1, and dentate gyrus (DG) after different pretreatments with RAP in immature rats. KEY FINDINGS: We found the following: (1) RAP administered with short-term pretreatment paradigms has a weak anticonvulsant potential in the seizure models with compromised inhibition. (2) Lack of RAP efficacy correlates with decreased NPY expression in the cortex, CA1, and DG. Specifically in immature rats, a single dose of RAP (3 mg/kg) 4 or 24 h before seizure testing had anticonvulsant effects against PTZ-induced seizures. In the flurothyl seizure model only the 4-h pretreatment with RAP was anticonvulsant in the both age groups. Short-term pretreatments with RAP had no effects against NMDA- and KA-induced seizures tested in immature rats. Long-term pretreatments with RAP over 8 days did not show beneficial effect in all tested seizure models in developing rats. Moreover, the long-term pretreatment with RAP had a slight proconvulsant effect on KA-induced seizures. In immature rats, any lack of anticonvulsant effect (including proconvulsant effect of multiple doses of RAP) was associated with downregulation of NPY expression in the cortex and DG. In immature animals, after a single dose of RAP with 24 h delay, we found a decrease of NPY expression in DG, and CA1 as well. SIGNIFICANCE: Our data show weak age-, treatment paradigm-, and model-specific anticonvulsant effects of RAP as well as loss of those effects after long-term RAP pretreatment associated with downregulation of NPY expression. These findings suggest that RAP is a poor anticonvulsant and may have beneficial effects only against epileptogenesis. In addition, our data present new insights into mechanisms of RAP action on seizures indicating a possible connection between mammalian target of rapamycin (mTOR) signaling and NPY system.

Model of cryptogenic infantile spasms after prenatal corticosteroid priming.

Infantile spasms (IS) is a devastating epilepsy syndrome of childhood. IS occurs in 3-12-month-old infants and is characterized by spasms, interictal electroencephalography (EEG) hypsarrhythmia, and profound mental retardation. Hormonal therapy [adrenocorticotropic hormone (ACTH), corticosteroids] is frequently used, but its efficacy is tainted by severe side effects. For research of novel therapies, a validated animal model of IS is required. We propose the model of spastic seizures triggered by N-methyl-d-aspartate (NMDA) in infant rats prenatally exposed to betamethasone. The spasms have remarkable similarity to human IS, including motor flexion spasms, ictal EEG electrodecrement, and responsiveness to ACTH. Interestingly, the spasms do not involve the hippocampus. Autoradiographic metabolic mapping as well as tagging of the areas of neuronal excitation with c-fos indicates a strong involvement of hypothalamic structures such as the arcuate nucleus, which has significant bilateral connections with other hypothalamic nuclei as well as with the brainstem.

Metabolic environment in substantia nigra reticulata is critical for the expression and control of hypoglycemia-induced seizures.

Seizures represent a common and serious complication of hypoglycemia. Here we studied mechanisms of control of hypoglycemic seizures induced by insulin injection in fasted and nonfasted rats. We demonstrate that fasting predisposes rats to more rapid and consistent development of hypoglycemic seizures. However, the fasting-induced decrease in baseline blood glucose concentration cannot account for the earlier onset of seizures in fasted versus nonfasted rats. Data obtained with c-Fos immunohistochemistry and [14C]2-deoxyglucose uptake implicate a prominent involvement of the substantia nigra reticulata (SNR) among other structures in the hypoglycemic seizure control. This is supported by data showing that fasting decreases the SNR expression of K(ATP) channels, which link metabolism with activity, and is further confirmed with microinfusions of K(ATP) channel agonist and antagonist. Data obtained with whole-cell and perforated patch recordings from SNR neurons in slices in vitro demonstrate that both presynaptic and postsynaptic K(ATP) channels participate in the failure of the SNR to control hypoglycemic seizures. The results suggest that fasting and insulin-induced hypoglycemia can lead to impairment in the function of the SNR, leading thus to hypoglycemic seizures.

The involvement of the substantia nigra pars reticulata in hypoglycemic seizures.

Neurological complications of hypoglycemia often include seizures and fasting is a predisposing factor for seizures to occur. The mechanisms involved are unknown. In rats, insulin administration induces hypoglycemia, which may lead to generalized seizures with barrel rotations as a hallmark. Here we compared the incidence of barrel rotations in fasted and nonfasted rats. Further, we investigated the role of the substantia nigra pars reticulata (SNR) in control of barrel rotations using localized bilateral microinfusions of GABA(A) or GABA(B) receptor agonists (muscimol or baclofen, respectively) or an N-methyl-D-aspartate (NMDA) receptor antagonist (AP7). The incidence of barrel rotations was significantly higher in fasted compared to nonfasted rats. SNR infusions of muscimol were ineffective, while both baclofen and AP7 significantly decreased occurrence of barrel rotations. These data suggest that during hypoglycemia, the SNR seizure controlling system has different properties than in seizure models not involving a metabolic stress.