Neuroscience
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The pathological hallmark of Parkinson's disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and the resulting striatal dopamine deficiency, which are responsible for the classic motor features. Although a diagnosis of PD relies on the clinical effects of dopamine deficiency, this disease is also associated with other neurotransmitter deficits that are recognized as causing various motor and non-motor symptoms. However, the cause of dopaminergic nigral neurodegeneration in PD and the underlying mechanisms remain unknown. ⋯ The short- (6-day) and long-term (32-day) progression of motor alterations was studied. This model leads to a bilateral and progressive increase in catalepsy (evident from the 3rd infusion in the short-term groups (p<0.01) and from the 7th infusion in the long-term groups (p<0.01), which was associated with a progressive nigrostriatal dopaminergic deficit. All together this makes the new model an interesting experimental tool to investigate the mechanisms involved in the progression of dopaminergic neurodegeneration.
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Corticotropin-releasing factor (CRF) signaling through CRF receptor 1 (CRFR1) regulates autonomic, endocrine and behavioral responses to stress and has been implicated in the pathophysiology of several disorders including anxiety, depression, and addiction. Using a validated CRFR1 reporter mouse line (bacterial artificial chromosome identified by green fluorescence protein (BAC GFP-CRFR1)), we investigated the distribution of CRFR1 in the developing mouse forebrain. Distribution of CRFR1 was investigated at postnatal days (P) 0, 4, and 21 in male and female mice. ⋯ We report a sexually dimorphic expression of CRFR1 within the rostral portion of the anteroventral periventricular nucleus of the hypothalamus (AVPV/PeN), a region known to regulate ovulation, reproductive and maternal behaviors. Females had a greater number of CRFR1-GFP-ir cells at all time points in the AVPV/PeN and CRFR1-GFP-ir was nearly absent in males by P21. Overall, alterations in CRFR1-GFP-ir distribution based on age and sex may contribute to observed age- and sex-dependent differences in stress regulation.
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Following tissue injury, phosphorylation of p38 MAPK in the primary afferent neurons drives sensitization of peripheral nerve. Dexmedetomidine extends the duration of reginal analgesia by local anesthetics. The effect of regional analgesia on the peripheral nerve sensitization is not known. ⋯ Levobupivacaine without dexmedetomidine could not inhibit p38 MAPK phosphorylation in the DRG completely. However, Levobupivacaine and dexmedetomidine completely inhibited p38 MAPK phosphorylation, and reduced macrophage accumulation and TNF-α amount in the plantar tissue. Inhibition of p38 MAPK phosphorylation via TNF-α suggests dexmedetomidine has a peripheral mechanism of anti-inflammatory action when used asan adjunct to local anesthetics, and provides a molecular basis for the prevention of peripheral sensitization following surgery.
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Cortical spreading depolarization (CSD) has an important role in brain diseases such as stroke, subarachnoid hemorrhage, migraine with aura, and epilepsy. Several anti-epileptic drugs (AEDs) are used to treat paroxysmal brain diseases and are thus known to suppress CSD. One of these AEDs is gabapentin (GBP) which has been traditionally used for treatment of some CSD-related neurological diseases. ⋯ These data support an effect of GBP on GABA-mediated inhibition in the late hyperexcitable phase of CSD. Modulations of synaptic properties and post-CSD GABAergic function are likely GBP's mechanisms of action in CSD-related disorders. These mechanisms could be targeted for further drug discovery in CSD-related diseases.
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Whether the CD38/cyclic ADP-ribose (cADPR) pathway plays a protective or detrimental role in neuroinflammation remains controversial. This study aimed to determine the role of CD38 in neuroinflammation using lipopolysaccharide (LPS)-stimulated BV2 microglial cells and co-cultured Neuro-2a (N2a) cells. In monoculture experiments, BV2 cells were divided into control, CD38 interference (CD38Ri), negative control (NC), LPS, CD38Ri+LPS, NC+LPS and 8-Br-cADPR+LPS groups. ⋯ Co-culture with CD38 knockdown or 8-Br-cADPR-treated BV2 cells did not influence apoptosis or iNOS expression in N2a cells. In conclusion, our results indicate that blocking the CD38/cADPR pathway reduces intracellular Ca2+, NO and the secretion of proinflammatory cytokines. CD38 knockdown exerted a detrimental effect in apoptosis and NO production in normal microglia, but played a protective role in apoptosis and NO production in LPS-stimulated microglia.