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Timing of therapies for Down syndrome: the sooner, the better.

Stagni F, Giacomini A, Guidi S, Ciani E, Bartesaghi R - Front Behav Neurosci (2015)

Bottom Line: Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation.Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation.For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna Bologna, Italy.

ABSTRACT
Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Accumulating evidence shows that DS is characterized by numerous neurodevelopmental alterations among which the reduction of neurogenesis, dendritic hypotrophy and connectivity alterations appear to play a particularly prominent role. Although the mechanisms whereby gene triplication impairs brain development in DS have not been fully clarified, it is theoretically possible to correct trisomy-dependent defects with targeted pharmacotherapies. This review summarizes what we know about the effects of pharmacotherapies during different life stages in mouse models of DS. Since brain alterations in DS start to be present prenatally, the prenatal period represents an optimum window of opportunity for therapeutic interventions. Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation. Although late therapies are unlikely to exert drastic changes in the brain, they may have an impact on the hippocampus, a brain region where neurogenesis continues throughout life. Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation. The exciting discovery that trisomy-linked brain abnormalities can be prevented with early interventions gives us reason to believe that treatments during pregnancy may rescue brain development in fetuses with DS. For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects. Prompt achievement of this goal is the big challenge for the scientific community of researchers interested in DS.

No MeSH data available.


Related in: MedlinePlus

Pharmacotherapies in the Ts65Dn mouse model of Down syndrome. (A) The histogram shows the number of attempted pharmacotherapies in the Ts65Dn mouse model of DS that rescued (Rescued), improved (Improved), partially rescued (Failed/Rescued) the examined phenotype/s or had no effect (Failed). Data derive from Tables 1, 2. (B) The histogram shows the number of studies in which pharmacotherapies were administered at adult life stages, in the neonatal period and in the prenatal (in some instances plus post-natal) period. Data derive from Tables 1, 2.
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Figure 3: Pharmacotherapies in the Ts65Dn mouse model of Down syndrome. (A) The histogram shows the number of attempted pharmacotherapies in the Ts65Dn mouse model of DS that rescued (Rescued), improved (Improved), partially rescued (Failed/Rescued) the examined phenotype/s or had no effect (Failed). Data derive from Tables 1, 2. (B) The histogram shows the number of studies in which pharmacotherapies were administered at adult life stages, in the neonatal period and in the prenatal (in some instances plus post-natal) period. Data derive from Tables 1, 2.

Mentions: By looking at Tables 1, 2 it appears that a variety of different agents, that act on different targets, can rescue one or more of the DS brain phenotypes. For instance, memory can be improved by antagonizing GABA receptors (Table 1) or by antagonizing the NMDA receptor (Table 1); neurogenesis can be increased by drugs that interact with GSK3β, such as lithium (Table 1), or drugs that interact with the serotonergic system, such as fluoxetine (Tables 1, 2). The outcomes of the studies reported in Table 1 are summarized in Figure 3A. Importantly, 36 out of 58 interventions obtained the full rescue of the examined phenotype (Figure 3A, Rescued); 11 interventions obtained an improvement (Figure 3A, Improved); four interventions obtained the rescue of some of the examined phenotypes but not others (Figure 3A, Failed/Rescued); and only seven interventions were ineffective (Figure 3A, Failed). It must be observed that the studies reported in Table 1 used mice of different ages and treatments with different durations. Thus, it cannot be ruled out that the ineffectiveness of some treatments may be related to the age of mice and/or to an insufficient treatment duration. In addition, it must be emphasized that the results of treatment (“rescue,” “improvement” and “failure”) reported in the column “Outcome” of Table 1 refer to the specific phenotype indicated in the first column. We must be aware that the rescue of a given phenotypic feature may not necessarily lead to a cognitive improvement. Although we take these limitations into account, if we group together interventions that elicit a rescue or an improvement of the observed phenotype/s it ensures that 51 out of 58 interventions (88%) have a positive impact on the DS brain. We believe that this is an extremely important success that may give new hope for DS.


Timing of therapies for Down syndrome: the sooner, the better.

Stagni F, Giacomini A, Guidi S, Ciani E, Bartesaghi R - Front Behav Neurosci (2015)

Pharmacotherapies in the Ts65Dn mouse model of Down syndrome. (A) The histogram shows the number of attempted pharmacotherapies in the Ts65Dn mouse model of DS that rescued (Rescued), improved (Improved), partially rescued (Failed/Rescued) the examined phenotype/s or had no effect (Failed). Data derive from Tables 1, 2. (B) The histogram shows the number of studies in which pharmacotherapies were administered at adult life stages, in the neonatal period and in the prenatal (in some instances plus post-natal) period. Data derive from Tables 1, 2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4594009&req=5

Figure 3: Pharmacotherapies in the Ts65Dn mouse model of Down syndrome. (A) The histogram shows the number of attempted pharmacotherapies in the Ts65Dn mouse model of DS that rescued (Rescued), improved (Improved), partially rescued (Failed/Rescued) the examined phenotype/s or had no effect (Failed). Data derive from Tables 1, 2. (B) The histogram shows the number of studies in which pharmacotherapies were administered at adult life stages, in the neonatal period and in the prenatal (in some instances plus post-natal) period. Data derive from Tables 1, 2.
Mentions: By looking at Tables 1, 2 it appears that a variety of different agents, that act on different targets, can rescue one or more of the DS brain phenotypes. For instance, memory can be improved by antagonizing GABA receptors (Table 1) or by antagonizing the NMDA receptor (Table 1); neurogenesis can be increased by drugs that interact with GSK3β, such as lithium (Table 1), or drugs that interact with the serotonergic system, such as fluoxetine (Tables 1, 2). The outcomes of the studies reported in Table 1 are summarized in Figure 3A. Importantly, 36 out of 58 interventions obtained the full rescue of the examined phenotype (Figure 3A, Rescued); 11 interventions obtained an improvement (Figure 3A, Improved); four interventions obtained the rescue of some of the examined phenotypes but not others (Figure 3A, Failed/Rescued); and only seven interventions were ineffective (Figure 3A, Failed). It must be observed that the studies reported in Table 1 used mice of different ages and treatments with different durations. Thus, it cannot be ruled out that the ineffectiveness of some treatments may be related to the age of mice and/or to an insufficient treatment duration. In addition, it must be emphasized that the results of treatment (“rescue,” “improvement” and “failure”) reported in the column “Outcome” of Table 1 refer to the specific phenotype indicated in the first column. We must be aware that the rescue of a given phenotypic feature may not necessarily lead to a cognitive improvement. Although we take these limitations into account, if we group together interventions that elicit a rescue or an improvement of the observed phenotype/s it ensures that 51 out of 58 interventions (88%) have a positive impact on the DS brain. We believe that this is an extremely important success that may give new hope for DS.

Bottom Line: Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation.Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation.For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna Bologna, Italy.

ABSTRACT
Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Accumulating evidence shows that DS is characterized by numerous neurodevelopmental alterations among which the reduction of neurogenesis, dendritic hypotrophy and connectivity alterations appear to play a particularly prominent role. Although the mechanisms whereby gene triplication impairs brain development in DS have not been fully clarified, it is theoretically possible to correct trisomy-dependent defects with targeted pharmacotherapies. This review summarizes what we know about the effects of pharmacotherapies during different life stages in mouse models of DS. Since brain alterations in DS start to be present prenatally, the prenatal period represents an optimum window of opportunity for therapeutic interventions. Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation. Although late therapies are unlikely to exert drastic changes in the brain, they may have an impact on the hippocampus, a brain region where neurogenesis continues throughout life. Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation. The exciting discovery that trisomy-linked brain abnormalities can be prevented with early interventions gives us reason to believe that treatments during pregnancy may rescue brain development in fetuses with DS. For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects. Prompt achievement of this goal is the big challenge for the scientific community of researchers interested in DS.

No MeSH data available.


Related in: MedlinePlus