Neuroscience
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The cytokine transforming growth factor alpha (TGF alpha) has proangiogenic and proneurogenic effects and can potentially reduce infarct volumes. Therefore, we administered TGF alpha or vehicle directly into the area surrounding the infarct in female mice that received gender-mismatched bone marrow transplants from green fluorescent protein (GFP)-expressing males prior to undergoing permanent middle cerebral artery occlusion. Newborn cells were tracked with bromodeoxyuridine (BrdU) labeling and immunohistochemistry at 90 days after stroke onset. ⋯ Our results also show that infarct size was significantly reduced in animals treated with TGF alpha compared with controls. These results suggest that TGF alpha can induce angiogenesis, neurogenesis and neuroprotection after stroke. At least part of the pro-angiogenic effect appears to be secondary to the incorporation of bone marrow-derived endothelial cells into blood vessels in the infarct border zone.
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Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic growth factor, which also has profound effects on the diseased CNS. G-CSF has been shown to enhance recovery from neurologic deficits in rodent models of ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization of bone marrow-derived cells and by its direct actions on CNS cells. ⋯ To explain the G-CSF triggered amyloid reduction and associated reversal of cognitive impairment, several mechanisms of action were explored. (1) G-CSF was hypothesized to increase activation of resident microglia and to increase mobilization of marrow-derived microglia. The effect of G-CSF on microglial activation was examined by quantitative measurements of total microglial burden. To determine if G-CSF increased trafficking of marrow-derived microglia into brain, bone marrow-derived green fluorescent protein-expressing (GFP+) microglia were visualized in the brains of chimeric AD mice. (2) To assess the role of immune-modulation in mediating G-CSF effects, a panel of cytokines was measured in both plasma and brain. (3) To test the hypothesis that reduction of A beta deposits can affect synaptic area, quantitative measurement of synaptophysin immunoreactivity in hippocampal CA1 and CA3 sectors was undertaken. (4) To learn whether enhanced hippocampal neurogenesis was induced by G-CSF treatment, numbers of calretinin-expressing cells were determined in dentate gyrus.
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Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. ⋯ The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.
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An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic interneurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status epilepticus induced by kainic acid. ⋯ Surviving interneurons increase their expression of GAD and the alpha1 GABA(A) receptor subunit, but this does not compensate for the interneuronal loss; the result is a dramatic reduction of tonic inhibition in the BLA circuitry. As activation of GluK1Rs by ambient levels of glutamate facilitates GABA release, the reduced level and function of these receptors may contribute to the reduction of tonic inhibitory activity. These alterations at a relatively early stage of epileptogenesis may facilitate the progress towards the development of epilepsy.
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Recent studies have shown that in the pedunculopontine tegmental nucleus (PPT), increased neuronal activity and kainate receptor-mediated activation of intracellular protein kinase A (PKA) are important physiological and molecular steps for the generation of rapid eye movement (REM) sleep. In the present study performed on rats, phosphorylated cyclic AMP response element-binding protein (pCREB) immunostaining was used as a marker for increased intracellular PKA activation and as a reflection of increased neuronal activity. To identify whether activated cells were either cholinergic or noncholinergic, the PPT and laterodorsal tegmental nucleus (LDT) cells were immunostained for choline acetyltransferase (ChAT) in combination with pCREB or c-Fos. ⋯ These results provide evidence supporting the hypothesis that during REM sleep, the PPT cholinergic neurons are active, whereas the LC and DRN neurons are inactive. More importantly, the regression analysis indicated that pCREB activation in approximately 98% of PPT cholinergic neurons, was caused by REM sleep. Moreover the results indicate that during REM sleep, PPT intracellular PKA activation and a transcriptional cascade involving pCREB occur exclusively in the cholinergic neurons.