No abstract

Anti-parkinsonian agents, pramipexole (PPX) and ropinirole (ROP), have been reported to possess neuroprotective properties, both in vitro and in vivo. The mechanisms underlying neuroprotection afforded by the D3-preferring receptor agonists remain poorly understood. The present study demonstrates that incubation of primary mesencephalic cultures with PPX and ROP or the conditioned medium from PPX- or ROP-treated primary cultures induced a marked increase in the number of dopamine (DA) neurons in the cultures. Similar effects can be observed after incubating with the conditioned medium derived from PPX- and ROP-treated substantia nigra astroglia. Meanwhile, PPX and ROP can protect the primary cells from insult of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Furthermore, the neurotrophic effects of PPX and ROP on mesencephalic dopamine neurons could be significantly blocked by D3 receptor antagonist, but not by D2 receptor antagonist. Moreover, we found that the levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the conditioned medium of mesencephalic cultures treated with PPX and ROP were significantly increased. Blocking GDNF and BDNF with the neutralizing antibodies, the neurotrophic effects of PPX and ROP were greatly diminished. These results suggest that D3 dopamine receptor-preferring agonists, PPX and ROP, exert neurotrophic effects on cultured DA neurons by modulating the production of endogenous GDNF and BDNF, which may participate in their neuroprotection.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile beta-amyloid (Abeta) plaques and cognitive decline. Neurogenesis in the adult hippocampus is implicated in regulating learning and memory, and is increased in human postmortem brain of AD patients. However, little is currently known about the changes of hippocampal neurogenesis in the progression of AD. As brain tissues from patients during the progression of AD are generally not available, an amyloid precursor protein (APP)/presenilin1 (PS1) double transgenic mouse model of AD was studied. Bromodeoxyuridine (BrdU) labeling supported by doublecortin staining was used to detect proliferating hippocampal cells in the mice. Compared with age-matched wild-type controls, 9-month-old transgenic mice with memory impairment and numerous brain Abeta deposits showed increased numbers of proliferating hippocampal cells. However, 3-month-old transgenic mice with normal memory and subtle brain Abeta deposits showed normal hippocampal proliferation. Double immunofluorescent labeling with BrdU and either NeuN or glial fibrillary acidic protein was conducted in mice at 10 months (28 days after the last BrdU injection) to determine the differentiation of proliferating cells. The number of hippocampal BrdU-positive cells and BrdU-positive cells differentiating into neurons (neurogenesis) in 10-month-old mice was greater in transgenic mice compared with age-matched controls, but the ratio of hippocampal BrdU-positive cells differentiating into neurons and astroglia was comparable. These results suggest hippocampal neurogenesis may increase during the progression of AD. Targeting this change in neurogenesis and understanding the underlying mechanism could lead to the development of a new treatment to control the progression of AD.

No abstract

Results suggest that in the socio-cultural context for Chinese, irrespective of their literacy skills, CAMSE proved feasible for use in clinical settings for dementia screening.

Recent evidence showed that epileptic seizures increase hippocampal neurogenesis in the adult rat, but prolonged seizures result in the aberrant hippocampal neurogenesis that often leads to a recurrent excitatory circuitry and thus contributes to epileptogenesis. However, the mechanism underlying the aberrant neurogenesis after prolonged seizures remains largely unclear. In this study, we examined the role of activated astrocytes and microglia in the aberrant hippocampal neurogenesis induced by status epilepticus. Using a lithium-pilocarpine model to mimic human temporal lobe epilepsy, we found that status epilepticus induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures. Then, we injected fluorocitrate stereotaxicly into the dentate hilus to inhibit astrocytic metabolism and found that fluorocitrate failed to prevent the seizure-induced formation of ectopic hilar basal dendrites but instead promoted the degeneration of dentate granule cells after seizures. In contrast, a selective inhibitor of microglia activation, minocycline, inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus. Furthermore, with stereotaxic injection of lipopolysaccharide into the intact dentate hilus to activate local microglia, we found that lipopolysaccharide promoted the development of ectopic hilar basal dendrites in the hippocampus. These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons and that minocycline could be a potential drug to impede seizure-induced aberrant migration of newborn neurons.

No abstract

Inflammatory responses in the brain are involved in the etiopathogenesis and sequelae of seizures. Ligation of microglial CD40 plays a role in the development of inflammatory responses in the central nervous system (CNS). Our study showed that there was an increased CD40 expression on activated microglia in the brain injury after lithium pilocarpine-induced status epilepticus (SE) in rats. Since peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a regulator of CNS inflammation and a powerful pharmacological target for counteracting CNS diseases, we investigated the role of the PPARgamma agonist, rosiglitazone, in the modulation of CD40 expression and in the pathological processes of inflammation after SE. We found that rosiglitazone inhibited the expression of CD40, tumor necrosis factor (TNF-alpha), and microglial activation in different regions of hippocampus. The results were indicated by immunohistochemistry, Western blot, and ELISA, respectively. Rosiglitazone also prevented neuronal loss in the CA1 area after SE observed by Nissl-staining. These protective effects were significantly reversed by the co-treatment with T0070907, a selective antagonist of the PPARgamma, which clearly demonstrated a PPARgamma-dependent mechanism. Our data provide evidence that rosiglitazone considerably attenuates inflammatory responses after SE by suppressing CD40 expression and microglial activation. Our data also support the idea that rosiglitazone might be a potential neuroprotective agent in epilepsy.