Neuropathological consequences of delivering an adenoviral vector in the rat brain

McMenamin, M M; Lantos, T; Carter, E E; Hamilton, Lucy R; Charlton, H. M.; Gonzalez, S C; Wood, Matthew

doi:10.1002/jgm.564

Cited by 5 publications

(3 citation statements)

References 53 publications

(67 reference statements)

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“…The functionality of the adenoviral A-CREB-expressing vector was established in a previous study: a CREB-expressing vector but not the A-CREB vector protected cells from excitotoxic and ischemic stress (Glover et al, 2004). Although adenoviral transduction has been used previously in behavioral studies, such as those investigating restoration of motor function in animal models of dopamine depletion (Umegaki et al, 1997;McMenamin et al, 2004), to our knowledge, this is the first time it has been used to demonstrate an interference with recognition memory.…”

Section: Discussionmentioning

confidence: 95%

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

Warburton¹,

Glover²,

Massey³

et al. 2005

J. Neurosci.

105

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We established the importance of phosphorylation of cAMP responsive element-binding protein (CREB) to both the familiarity discrimination component of long-term recognition memory and plasticity within the perirhinal cortex of the temporal lobe. Adenoviral transduction of perirhinal cortex (and adjacent visual association cortex) with a dominant-negative inhibitor of CREB impaired the preferential exploration of novel over familiar objects at a long (24 h) but not a short (15 min) delay, disrupted the normal reduced activation of perirhinal neurons to familiar compared with novel pictures, and impaired long-term potentiation of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for involvement of CREB phosphorylation in synaptic plastic processes within perirhinal cortex necessary for long-term recognition memory.

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Section: Discussionmentioning

confidence: 95%

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

Warburton¹,

Glover²,

Massey³

et al. 2005

J. Neurosci.

105

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“…adenovirus-mediated gene therapy has been tested as a potential treatment for Parkinson's disease in animal models. It is suggested that the outcome of gene transfection can depend on the physiological state of target cells and tissue [15,16]. It is possible that in the experimental models of PD the success of gene therapy could be affected by the condition of nigrostriatal cells, too.…”

Section: Resultsmentioning

confidence: 99%

Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

Raasmaja¹,

Lehtonen²,

Kääriäinen³

et al. 2013

OJGen

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The use of gene therapy has been intensively studied as a potential method to treat Parkinson's disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the outcome of gene delivery or on the physiological state of target tissues have not been analyzed as much and systematically. Therefore, we have infused adenovirus vectors expressing either a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into striatum in a rat model of PD. The experimental procedures were tested using the Ad lacZ vector in order to optimize concentrations, volumes, infusion speeds and transfection times. The expression of Ad lacZ vector was lower and declined earlier in the lesioned than unlesioned striatum suggesting that the lesion affects on the transfection efficiency and outcome of gene transfection. The effect of three different approaches of Ad TH vector transfection was compared: 1) the delivery of Ad TH gene vector alone into one single site of striatum, 2) the delivery of Ad TH gene vector alone into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into one site of striatum followed by a continuous infusion of tetrahydrobiopterin (BH4) cofactor with a mini pump. There was a small and transient unsignificant decrease in the turning behavior when the Ad TH vector was delivered into one site of the striatum. Simultaneous infusion into several sites or together with BH4 cofactor did not improve more the effect of gene delivery. Thus, although the effects were unsignificant, the Ad TH transfection seemed to decrease the turning behavior in the rat model of PD and the optimal effect was seen at some specific doses and time points. Furthermore, the outcome of gene therapy could depend in addition to the amount and efficacy of gene vectors also on the physiological state and experimental strategies.

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“…The toxicity of sustained ferritin over-expression may be mitigated by the use of adenoviral vectors, which tend to produce transient gene expression [39]. However, any benefit may then be negated by a direct cytotoxic or inflammatory response [40]. Further investigation is needed to determine if ferritin gene transfer is feasible in vivo, and if it also protects neurons and other vulnerable cell populations.…”

Section: Discussionmentioning

confidence: 99%

Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity

Chen-Roetling

Regan

2009

Free Radical Research

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Iron toxicity may contribute to oxidative injury in cells surrounding an intracerebral hematoma. Cells detoxify iron by sequestering it in ferritin, a 24-mer heteropolymer constructed of H and L subunits. The relative antioxidant efficacy of H and L-ferritin has not been defined, and was tested in this study using an established model of hemin toxicity. Consistent with prior observations, cultures treated with 30 μM hemin sustained loss of approximately half of cells by six hours, as measured by LDH and MTT assays, and a 14-fold increase in protein carbonyls. Increasing expression of either ferritin by adenoviral gene transfer prior to hemin treatment had a similar protective effect. Quenching of calcein fluorescence, a marker of the labile iron pool, in hemin-treated cultures was also equally reduced by either subunit. These results suggest that over-expression of either H or L ferritin protects astrocytes from hemin, and may be beneficial after CNS hemorrhage.

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Neuropathological consequences of delivering an adenoviral vector in the rat brain

Abstract: Neuropathological damage in the dopaminergic system, caused by high doses of adenoviral vectors, has not previously been documented. To minimise damage and prolong transgene expression, it is important that the dose of vectors to be delivered is carefully optimised.

Cited by 5 publications

References 53 publications

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity

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