A Novel Rat Model of ADHD-like Hyperactivity/Impulsivity after Delayed Reward Has Selective Loss of Dopaminergic Neurons in the Right Ventral Tegmental Area.

In attention deficit hyperactivity disorder (ADHD), hyperactivity and impulsivity occur in response to reward. Herein we report a novel animal model in which male Sprague-Dawley rats exposed to repeated hypoxic brain injury during the equivalent of extreme prematurity were ADHD-like hyperactive/impulsive in response to delayed reward and attentive at 3 months of age. Thus, a unique animal model of one of the presentations/subtypes of ADHD was discovered.

Vascular perfusion differs in two distinct PDGFRβ-positive zones within the ischemic core of male mice 2 weeks following photothrombotic stroke.

Stroke therapy has largely focused on preventing damage and encouraging repair outside the ischemic core, as the core is considered irreparable. Recently, several studies have suggested endogenous responses within the core are important for limiting the spread of damage and enhancing recovery, but the role of blood flow and capillary pericytes in this process is unknown. Using the Rose Bengal photothrombotic model of stroke, we illustrate blood vessels are present in the ischemic core and peri-lesional regions 2 weeks post stroke in male mice.

The CaMKIIα hub ligand Ph-HTBA promotes neuroprotection after focal ischemic stroke by a distinct molecular interaction.

Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a potential target for acute neuroprotection due to its key role in physiological and pathological glutamate signaling. The hub domain organizes the CaMKII holoenzyme into large oligomers, and additional functional effects on holoenzyme activation have lately emerged. We recently reported that compounds related to the proposed neuromodulator γ-hydroxybutyrate (GHB) selectively bind to the CaMKIIα hub domain and increase hub thermal stabilization, which is believed to have functional consequences and to mediate neuroprotection.

Neuroprotective activity of new Δ3-N-acylethanolamines in a focal ischemia stroke model.

N-acylethanolamines (NAE, also called ethanolamides) are significant lipid signaling molecules with anti-inflammatory, pain-relieving, cell-protective, and anticancer properties. Here, we present the use of a hitherto unreported group of Δ3-NAE and also some Δ4- and Δ5-NAE, in in vitro and in vivo assays to gain a better understanding of their structure-bioactivity relationships. We have developed an efficient synthetic method to rapidly produce novel unlabeled and C-labeled Δ3-NAE (NAE-18:5n-3, NAE-18:4n-6) and Δ4-NAE (NAE-22:5n-6).

GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.

Ca/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα.

Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice.

The extracellular matrix fragment perlecan domain V is neuroprotective and functionally restorative following experimental stroke. As neurogenesis is an important component of chronic post-stroke repair, and previous studies have implicated perlecan in developmental neurogenesis, we hypothesized that domain V could have a broad therapeutic window by enhancing neurogenesis after stroke. We demonstrated that domain V is chronically increased in the brains of human stroke patients, suggesting that it is present during post-stroke neurogenic periods.

The Delta-Subunit Selective GABA Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism.

Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABA receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation.

Altered Hippocampal-Prefrontal Dynamics Following Medial Prefrontal Stroke in Mouse.

Frontal infarcts can produce cognitive impairments that affect an individual's ability to function in everyday life. However, the precise types of deficits, and their underlying mechanisms, are not well-understood. Here we used a prefrontal photothrombotic stroke model in C57BL/6J mice to characterise specific cognitive changes that occur in the 6 weeks post-stroke.

Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice.

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition.

Age-dependent Disturbances of Neuronal and Glial Protein Expression Profiles in Areas of Secondary Neurodegeneration Post-stroke.

Despite the fact that approximately 80% of strokes occur in those aged over 60 years, many pre-clinical stroke studies have been conducted in younger adult rodents, raising debate about translation and generalizability of these results. We were interested in potential age differences in stroke-induced secondary neurodegeneration (SND). SND involves the death of neurons in areas remote from, but connected to, the site of infarction, as well as glial disturbances.

Effects of nidopallium caudolaterale inactivation on serial-order behavior in pigeons ( Columba livia).

Serial-order behavior is the ability to complete a sequence of responses in a predetermined order to achieve a reward. In birds, serial-order behavior is thought to be impaired by damage to the nidopallium caudolaterale (NCL). In the current study, we examined the role of the NCL in serial-order behavior by training pigeons on a 4-item serial-order task and a go/no-go discrimination task.

Dietary nitrate supplementation reduces low frequency blood pressure fluctuations in rats following distal middle cerebral artery occlusion.

It is known that high blood pressure variability (BPV) in acute ischemic stroke is associated with adverse outcomes, yet there are no therapeutic treatments to reduce BPV. Studies have found increasing nitric oxide (NO) bioavailability improves neurological function following stroke, but whether dietary nitrate supplementation could reduce BPV remains unknown. We investigated the effects of dietary nitrate supplementation on heart rate (HR), blood pressure (BP), and beat-to-beat BPV using wireless telemetry in a rat model of distal middle cerebral artery occlusion.

Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke.

Background And Purpose: Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke.

Methods: We tested the efficacy of acute (1.

The flavonoid, 2'-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia.

Tonic inhibitory currents, mediated by extrasynaptic GABA receptors, are elevated at a delay following stroke. Flavonoids minimise the extent of cellular damage following stroke, but little is known about their mode of action. We demonstrate that the flavonoid, 2'-methoxy-6-methylflavone (0.

GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice.

Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke.

Inhibition of GABA transporters fails to afford significant protection following focal cerebral ischemia.

Brain ischemia triggers excitotoxicity and cell death, yet no neuroprotective drugs have made it to the clinic. While enhancing GABAergic signaling to counterbalance excitotoxicity has shown promise in animal models, clinical studies have failed. Blockade of GABA transporters (GATs) offers an indirect approach to increase GABA inhibition to lower the excitation threshold of neurons.

Sonic hedgehog stimulates neurite outgrowth in a mechanical stretch model of reactive-astrogliosis.

Although recovery following a stroke is limited, undamaged neurons under the right conditions can establish new connections and take on-board lost functions. Sonic hedgehog (Shh) signaling is integral for developmental axon growth, but its role after injury has not been fully examined. To investigate the effects of Shh on neuronal sprouting after injury, we used an in vitro model of glial scar, whereby cortical astrocytes were mechanically traumatized to mimic reactive astrogliosis observed after stroke.

Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia.

Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies.

Combined ampakine and BDNF treatments enhance poststroke functional recovery in aged mice via AKT-CREB signaling.

Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective.

Perlecan domain V is neuroprotective and affords functional improvement in a photothrombotic stroke model in young and aged mice.

With the failure of so many pre-clinical stroke studies to translate into the clinic, there is a need to find new therapeutics to minimize the extent of cellular damage and aid in functional recovery. Domain V (DV), the c-terminal protein fragment of the vascular basement membrane component, perlecan, was recently shown to afford significant protection in multiple transient middle cerebral artery occlusion stroke models. We sought here to determine whether DV might have similar therapeutic properties in a focal photothrombosis stroke model in both young and aged mice.