Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury.

Traumatic Brain Injury (TBI) remains a leading cause of morbidity and mortality in adults under 40 years old. Once primary injury occurs after TBI, neuroinflammation and oxidative stress (OS) are triggered, contributing to the development of many TBI-induced neurological deficits, and reducing the probability of critical trauma patients´ survival. Regardless the research investment on the development of anti-inflammatory and neuroprotective treatments, most pre-clinical studies have failed to report significant effects, probably because of the limited blood brain barrier permeability of no-steroidal or steroidal anti-inflammatory drugs. Lately, neurotrophic factors, such as the insulin-like growth factor 1 (IGF-1), are considered attractive therapeutic alternatives for diverse neurological pathologies, as they are neuromodulators linked to neuroprotection and anti-inflammatory effects. Considering this background, the aim of the present investigation is to test early IGF-1 gene therapy in both OS markers and cognitive deficits induced by TBI. Male Wistar rats were injected via Cisterna Magna with recombinant adenoviral vectors containing the IGF-1 gene cDNA 15 min post-TBI. Animals were sacrificed after 60 min, 24 h or 7 days to study the advanced oxidation protein products (AOPP) and malondialdehyde (MDA) levels, to recognize the protein oxidation damage and lipid peroxidation respectively, in the TBI neighboring brain areas. Cognitive deficits were assessed by evaluating working memory 7 days after TBI. The results reported significant increases of AOPP and MDA levels at 60 min, 24 h, and 7 days after TBI in the prefrontal cortex, motor cortex and hippocampus. In addition, at day 7, TBI also reduced working memory performance. Interestingly, AOPP, and MDA levels in the studied brain areas were significantly reduced after IGF-1 gene therapy that in turn prevented cognitive deficits, restoring TBI-animals working memory performance to similar values regarding control. In conclusion, early IGF-1 gene therapy could be considered a novel therapeutic approach to targeting neuroinflammation as well as to preventing some behavioral deficits related to TBI.

Decrease of Rab11 prevents the correct dendritic arborization, synaptic plasticity and spatial memory formation.

Emerging evidence shows that Rab11 recycling endosomes (REs Rab11) are essential for several neuronal processes, including the proper functioning of growth cones, synapse architecture regulation and neuronal migration. However, several aspects of REs Rab11 remain unclear, such as its sub-cellular distribution across neuronal development, contribution to dendritic tree organization and its consequences in memory formation. In this work we show a spatio-temporal correlation between the endogenous localization of REs Rab11 and developmental stage of neurons. Furthermore, Rab11-suppressed neurons showed an increase on dendritic branching (without altering total dendritic length) and misdistribution of dendritic proteins in cultured neurons. In addition, suppression of Rab11 in adult rat brains in vivo (by expressing shRab11 through lentiviral infection), showed a decrease on both the sensitivity to induce long-term potentiation and hippocampal-dependent memory acquisition. Taken together, our results suggest that REs Rab11 expression is required for a proper dendritic architecture and branching, controlling key aspects of synaptic plasticity and spatial memory formation.

Early Cognitive Impairment Behind Nigrostriatal Circuit Neurotoxicity: Are Astrocytes Involved?

Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modifications in the plasticity and architecture of hippocampal synapses. Such alterations can be implicated in the genesis and progression of dementia associated with neurodegenerative diseases including Parkinson-like symptoms. There are few studies regarding cognitive changes in nigrostriatal animal models. The aim of this study was to characterize the onset of memory deficit after induction of neurotoxicity with 6-hydroxydopamine (6-OHDA) and its correlation with hippocampal dysfunction. For this, we bilaterally microinjected 6-OHDA in dorsolateral Caudate-Putamen unit (CPu) and then, animals were tested weekly for working memory, spatial short-term memory, and motor performance. We evaluated tyrosine hydroxylase (TH) as a dopamine marker, aldehyde dehydrogenase 2 (ALDH2), a mitochondria detoxification enzyme and astrocyte glial fibrillar acid protein (GFAP) an immunoreactivity marker involved in different areas: CPu, substantia nigra, prefrontal cortex, and hippocampus. We observed a specific prefrontal cortex and nigrostriatal pathway TH reduction while ALDH2 showed a decrease-positive area in all the studied regions. Moreover, GFAP showed a specific CPu decrease and hippocampus increase of positively stained area on the third week after toxicity. We also evaluated the threshold to induce long-term potentiation in hippocampal excitability. Our findings showed that reduced hippocampal synaptic transmission was accompanied by deficits in memory processes, without affecting motor performance on the third-week post 6-OHDA administration. Our results suggest that 3 weeks after neurotoxic administration, astrocytes and ALDH2 mitochondrial enzyme modifications participate in altering the properties that negatively affect hippocampal function and consequently cognitive behavior.

Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor.

RATIONALE: Ghrelin (Ghr) is a peptide that participates in the modulation of several biological processes. Ghr administration into the hippocampus improves learning and memory in different memory tests. However, the possible mechanisms underlying this effect on memory have not yet been clarified. OBJECTIVE: The purpose of the present work is to add new insights about the mechanisms by which Ghr modulates long-term memory consolidation in the hippocampus. We examined Ghr effects upon processes related to increased synaptic efficacy as presynaptic glutamate release and changes in the expression of the NR2B-subunits containing n-methyl-d-aspartate receptors (NMDAR), which are critical for LTP induction. We also attempted to determine the temporal window in which Ghr administration induces memory facilitation and if the described effects depend on GHS-R1a stimulation. RESULTS: The present research demonstrated that Ghr increased glutamate release from hippocampal synaptosomes; intra-hippocampal Ghr administration increased NR2B-subunits expression in CA1 and DG subareas and also reversed the deleterious effects of the NR2B-subunit-specific antagonist, Ro 25-6981, upon memory consolidation and LTP generation in the hippocampus. These effects are likely to be the consequence of GHS-R1a activation. CONCLUSION: According to the results above mentioned and previous findings, we can hypothesize some of the mechanisms by which Ghr modulates memory consolidation. At presynaptic level, Ghr stimulates glutamate release, probably by enhancing [Ca(2+)]i. At postsynaptic level, the glutamate released activates NMDAR while Ghr also mediates effects directly activating its specific receptors and increases NR2B-subunit expression.