SAHA Enhances Synaptic Function and Plasticity in Vitro but Has Limited Brain Availability in Vivo and Does Not Impact Cognition.

SAHA Enhances Synaptic Function and Plasticity In Vitro but Has Limited Brain Availability In Vivo and Does Not Impact Cognition.

PLoS One. 2013; 8(7): e69964
Hanson JE, La H, Plise E, Chen YH, Ding X, Hanania T, Sabath EV, Alexandrov V, Brunner D, Leahy E, Steiner P, Liu L, Scearce-Levie K, Zhou Q

Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer’s disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology. HubMed – depression

Electroconvulsive therapy induces neurogenesis in frontal rat brain areas.

PLoS One. 2013; 8(7): e69869
Inta D, Lima-Ojeda JM, Lau T, Tang W, Dormann C, Sprengel R, Schloss P, Sartorius A, Meyer-Lindenberg A, Gass P

Electroconvulsive therapy (ECT) is an effective therapy for several psychiatric disorders, including severe major depression, mania and certain forms of schizophrenia. It had been proposed that ECT acts by modulating local plasticity via the stimulation of neurogenesis. In fact, among antidepressant therapies, ECT is the most robust enhancer of neurogenesis in the hippocampus of rodents and non-human primates. The existence of ECT-triggered neurogenesis in other brain areas, particularly in those adjacent to the other main locus of neurogenesis, the subventricular zone (SVZ), had so far remained unknown. Here we show that ECT also strongly enhances neurogenesis in frontal brain areas, especially in the rostro-medial striatum, generating specific, small-size calretinin-positive interneurons. We provide here the first evidence that ECT stimulates neurogenesis in areas outside the hippocampus. Our data may open research possibilities that focus on the plastic changes induced by ECT in frontal limbic circuitry. HubMed – depression

Presence and significant determinants of cognitive impairment in a large sample of patients with multiple sclerosis.

PLoS One. 2013; 8(7): e69820
Borghi M, Cavallo M, Carletto S, Ostacoli L, Zuffranieri M, Picci RL, Scavelli F, Johnston H, Furlan PM, Bertolotto A, Malucchi S

To investigate the presence and the nature of cognitive impairment in a large sample of patients with Multiple Sclerosis (MS), and to identify clinical and demographic determinants of cognitive impairment in MS.303 patients with MS and 279 healthy controls were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N); measures of pre-morbid verbal competence and neuropsychiatric measures were also administered.Patients and healthy controls were matched for age, gender, education and pre-morbid verbal Intelligence Quotient. Patients presenting with cognitive impairment were 108/303 (35.6%). In the overall group of participants, the significant predictors of the most sensitive BRB-N scores were: presence of MS, age, education, and Vocabulary. The significant predictors when considering MS patients only were: course of MS, age, education, vocabulary, and depression. Using logistic regression analyses, significant determinants of the presence of cognitive impairment in relapsing-remitting MS patients were: duration of illness (OR?=?1.053, 95% CI?=?1.010-1.097, p?=?0.015), Expanded Disability Status Scale score (OR?=?1.247, 95% CI?=?1.024-1.517, p?=?0.028), and vocabulary (OR?=?0.960, 95% CI?=?0.936-0.984, p?=?0.001), while in the smaller group of progressive MS patients these predictors did not play a significant role in determining the cognitive outcome.Our results corroborate the evidence about the presence and the nature of cognitive impairment in a large sample of patients with MS. Furthermore, our findings identify significant clinical and demographic determinants of cognitive impairment in a large sample of MS patients for the first time. Implications for further research and clinical practice were discussed. HubMed – depression