Involvement of JNK1 in Neuronal Polarization During Brain Development.

The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural stem cells and ending with their final positioning when migrating and maturing. This review will focus mostly on isoform JNK1, the foremost contributor of total JNK activity in the CNS. Throughout the text, research from multiple groups will be summarized and discussed in order to describe the involvement of the JNKs in the different steps of neuronal polarization. The data presented support the idea that isoform JNK1 is highly relevant to the regulation of many of the processes that occur in neuronal development in the CNS.

Pirfenidone Attenuates Microglial Reactivity and Reduces Inducible Nitric Oxide Synthase mRNA Expression After Kainic Acid-Mediated Excitotoxicity in Pubescent Rat Hippocampus.

Excitotoxicity and neuroinflammation are strongly linked to the progressions of neurodegenerative diseases and acute injuries in the brain. Systematic administration of kainic acid (KA) in rodents causes severe limbic seizures, selective neuronal loss, and neuroinflammation in the hippocampus that are attributed to the excitotoxic process. Our previous report demonstrated the antioxidant and neuroprotective effects of pirfenidone (PFD) after the seizure onset induced by KA intraperitoneal injection. However, the aim of the present study is to analyze whether PFD has anti-inflammatory properties. Thus, pubescent male Wistar rats (30 days old) were exposed to 12 mg/Kg of KA, and the experimental group received KA and a single dose of 325 mg/Kg PFD in an orogastric tube at 90 min after KA exposure. The PFD treatment dramatically reduces the microglial activation observed by isolectin B4 staining and major histocompatibility complex II immunohistochemistry. We also determined that the messenger RNA of inducible nitric oxide synthase was downregulated by PFD treatment as measured 6 h after the KA injection. Our results indicate that the mechanism of neuroprotection after PFD treatment may include a decreased expression of the inducible nitric oxide synthase and reduced microglial activation. These findings suggest that PFD is a potentially useful strategy of the treatment for acute or chronic neurodegenerative diseases.

P38 MAPK inhibition protects against glutamate neurotoxicity and modifies NMDA and AMPA receptor subunit expression.

NMDA and AMPA receptors are thought to be responsible for Ca(++) influx during glutamate-induced excitotoxicity and, therefore, hippocampal neuronal death. We assessed whether excitotoxicity induced by neonatal treatment with monosodium glutamate in rats at postnatal age of 1, 3, 5, and 7 modifies the hippocampal expression of the NMDAR subunit NR1 and the AMPAR subunits GluR1/GluR2 at postnatal days 8, 10, 12, and 14. We also assessed the involvement of MAPK signaling by using the p38 inhibitor SB203580. Our results showed that monosodium glutamate induces neuronal death and alters the expression of the subunits evaluated in the hippocampus at all ages studied, which could be prevented by SB203580 treatment.Furthermore, expression of the NRSF gene silencing factor also increased in response to excitotoxicity, suggesting a relationship in suppressing GluR2-expression, which was regulated by the p38-MAPK pathway inhibitor SB203580. This result suggests that selectively blocking the pro-death signaling pathway may reduce neuronal death in some neurodegenerative diseases in which these neurotoxic processes are present and produce major clinical benefits in the treatment of these pathologies.

A single dose of pirfenidone attenuates neuronal loss and reduces lipid peroxidation after kainic acid-induced excitotoxicity in the pubescent rat hippocampus.

Systemic administration of kainic acid (KA) in rodents triggers limbic seizures following selective neuronal loss in the hippocampus attributed to the excitotoxic process. Lipid peroxidation products, such as 4-hydroxynonenal, are produced by oxidative stress and are present on the hippocampus, which contribute to neuronal death in the KA excitotoxicity model. Several antioxidants are neuroprotective agents. The aim of the present study was to analyse whether pirfenidone (PFD, 5-methyl-1-phenyl-2-(1H)-pyridone), an antioxidant drug, protects the neurons in the hippocampus of pubescent rats administered with KA. We evaluated the neuroprotective effect of PFD by quantifying the surviving neurons under hematoxilin-eosin staining after using three different doses of 100, 250, and 325 mg/kg administered via an orogastric tube 90 min after KA intraperitoneal injection (12 mg/kg). Only 325 mg/kg of PFD-attenuated neuronal loss in the hippocampal areas cornu ammonis field 1 (CA1) and cornu ammonis field 3 (CA3c) was observed; therefore, this dose was used in our subsequent studies. Later, we established that PFD reduces neuronal degeneration using Fluoro-Jade B stain in the CA3c but not in the CA1, and PFD reduces the presence of 4-hydroxynonenal, a lipid peroxidation product, in the CA3 by tissue immunohistochemistry. We concluded that only a single 325 mg/kg PFD dose had a neuroprotective effect after KA brain injury. This treatment may be advantageous because adequate pharmacological therapy with PFD can be developed to protect the neuron even after an acute neuronal disorder such as seizures or hypoxic/ischemic damage.