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Quinazoline-based tricyclic compounds that regulate programmed cell death, induce neuronal differentiation, and are curative in animal models for excitotoxicity and hereditary brain disease

View Article: PubMed Central - PubMed

ABSTRACT

Expanding on a quinazoline scaffold, we developed tricyclic compounds with biological activity. These compounds bind to the 18 kDa translocator protein (TSPO) and protect U118MG (glioblastoma cell line of glial origin) cells from glutamate-induced cell death. Fascinating, they can induce neuronal differentiation of PC12 cells (cell line of pheochromocytoma origin with neuronal characteristics) known to display neuronal characteristics, including outgrowth of neurites, tubulin expression, and NeuN (antigen known as ‘neuronal nuclei’, also known as Rbfox3) expression. As part of the neurodifferentiation process, they can amplify cell death induced by glutamate. Interestingly, the compound 2-phenylquinazolin-4-yl dimethylcarbamate (MGV-1) can induce expansive neurite sprouting on its own and also in synergy with nerve growth factor and with glutamate. Glycine is not required, indicating that N-methyl-D-aspartate receptors are not involved in this activity. These diverse effects on cells of glial origin and on cells with neuronal characteristics induced in culture by this one compound, MGV-1, as reported in this article, mimic the diverse events that take place during embryonic development of the brain (maintenance of glial integrity, differentiation of progenitor cells to mature neurons, and weeding out of non-differentiating progenitor cells). Such mechanisms are also important for protective, curative, and restorative processes that occur during and after brain injury and brain disease. Indeed, we found in a rat model of systemic kainic acid injection that MGV-1 can prevent seizures, counteract the process of ongoing brain damage, including edema, and restore behavior defects to normal patterns. Furthermore, in the R6-2 (transgenic mouse model for Huntington disease; Strain name: B6CBA-Tg(HDexon1)62Gpb/3J) transgenic mouse model for Huntington disease, derivatives of MGV-1 can increase lifespan by >20% and reduce incidence of abnormal movements. Also in vitro, these derivatives were more effective than MGV-1.

No MeSH data available.


Summary of the effects of MGV-1 in cell cultures of U118MG and PC12 cells. Glutamate (35 mM) induces cell death of U118MG cells as well PC12 cells (skulls in top boxes). MGV-1 protects U118MG cells from glutamate-induced cell death (crossed out skulls in left-hand bottom box). In contrast, MGV-1 together with glutamate induces pronounced neuronal differentiation of PC12 cells (image of a mature neuron in most right-hand bottom box). As shown in Figure 3, MGV-1 also enhances cell death induction of glutamate of PC12 cells. Thus, MGV-1 appears to be able to regulate astrocytic integrity, neuronal differentiation, and weeding out of non-differentiating progenitor cells.19,37
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fig8: Summary of the effects of MGV-1 in cell cultures of U118MG and PC12 cells. Glutamate (35 mM) induces cell death of U118MG cells as well PC12 cells (skulls in top boxes). MGV-1 protects U118MG cells from glutamate-induced cell death (crossed out skulls in left-hand bottom box). In contrast, MGV-1 together with glutamate induces pronounced neuronal differentiation of PC12 cells (image of a mature neuron in most right-hand bottom box). As shown in Figure 3, MGV-1 also enhances cell death induction of glutamate of PC12 cells. Thus, MGV-1 appears to be able to regulate astrocytic integrity, neuronal differentiation, and weeding out of non-differentiating progenitor cells.19,37

Mentions: Embryonic development of brain includes maintenance of a glial scaffold to support developing neurons.56 The neuronal development includes migration of enormous numbers of progenitor cells into specific target areas. Subsequently, millions of these cells reaching the target area die off, whereas only a very restricted number of progenitor cells (a few ten thousands) develop into mature neurons.29 In this study, the presented tricyclic compounds based on a quinazoline scaffold induced effects in cell culture that mimic those of embryonic brain development. This includes: (1) protecting cells of glial origin from cell death, (2) stimulating massive cell death of neuronal progenitor cells as induced by glutamate, and (3) stimulating extensive neuronal differentiation of the surviving neuronal progenitor cells (Figure 8). To emphasize, it appears that our relatively small tricyclic molecules basically can induce overall cell processes essential for brain development, as well as protect and cure adult brain damage. The latter was indeed demonstrated in our animal models.


Quinazoline-based tricyclic compounds that regulate programmed cell death, induce neuronal differentiation, and are curative in animal models for excitotoxicity and hereditary brain disease
Summary of the effects of MGV-1 in cell cultures of U118MG and PC12 cells. Glutamate (35 mM) induces cell death of U118MG cells as well PC12 cells (skulls in top boxes). MGV-1 protects U118MG cells from glutamate-induced cell death (crossed out skulls in left-hand bottom box). In contrast, MGV-1 together with glutamate induces pronounced neuronal differentiation of PC12 cells (image of a mature neuron in most right-hand bottom box). As shown in Figure 3, MGV-1 also enhances cell death induction of glutamate of PC12 cells. Thus, MGV-1 appears to be able to regulate astrocytic integrity, neuronal differentiation, and weeding out of non-differentiating progenitor cells.19,37
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979516&req=5

fig8: Summary of the effects of MGV-1 in cell cultures of U118MG and PC12 cells. Glutamate (35 mM) induces cell death of U118MG cells as well PC12 cells (skulls in top boxes). MGV-1 protects U118MG cells from glutamate-induced cell death (crossed out skulls in left-hand bottom box). In contrast, MGV-1 together with glutamate induces pronounced neuronal differentiation of PC12 cells (image of a mature neuron in most right-hand bottom box). As shown in Figure 3, MGV-1 also enhances cell death induction of glutamate of PC12 cells. Thus, MGV-1 appears to be able to regulate astrocytic integrity, neuronal differentiation, and weeding out of non-differentiating progenitor cells.19,37
Mentions: Embryonic development of brain includes maintenance of a glial scaffold to support developing neurons.56 The neuronal development includes migration of enormous numbers of progenitor cells into specific target areas. Subsequently, millions of these cells reaching the target area die off, whereas only a very restricted number of progenitor cells (a few ten thousands) develop into mature neurons.29 In this study, the presented tricyclic compounds based on a quinazoline scaffold induced effects in cell culture that mimic those of embryonic brain development. This includes: (1) protecting cells of glial origin from cell death, (2) stimulating massive cell death of neuronal progenitor cells as induced by glutamate, and (3) stimulating extensive neuronal differentiation of the surviving neuronal progenitor cells (Figure 8). To emphasize, it appears that our relatively small tricyclic molecules basically can induce overall cell processes essential for brain development, as well as protect and cure adult brain damage. The latter was indeed demonstrated in our animal models.

View Article: PubMed Central - PubMed

ABSTRACT

Expanding on a quinazoline scaffold, we developed tricyclic compounds with biological activity. These compounds bind to the 18 kDa translocator protein (TSPO) and protect U118MG (glioblastoma cell line of glial origin) cells from glutamate-induced cell death. Fascinating, they can induce neuronal differentiation of PC12 cells (cell line of pheochromocytoma origin with neuronal characteristics) known to display neuronal characteristics, including outgrowth of neurites, tubulin expression, and NeuN (antigen known as ‘neuronal nuclei’, also known as Rbfox3) expression. As part of the neurodifferentiation process, they can amplify cell death induced by glutamate. Interestingly, the compound 2-phenylquinazolin-4-yl dimethylcarbamate (MGV-1) can induce expansive neurite sprouting on its own and also in synergy with nerve growth factor and with glutamate. Glycine is not required, indicating that N-methyl-D-aspartate receptors are not involved in this activity. These diverse effects on cells of glial origin and on cells with neuronal characteristics induced in culture by this one compound, MGV-1, as reported in this article, mimic the diverse events that take place during embryonic development of the brain (maintenance of glial integrity, differentiation of progenitor cells to mature neurons, and weeding out of non-differentiating progenitor cells). Such mechanisms are also important for protective, curative, and restorative processes that occur during and after brain injury and brain disease. Indeed, we found in a rat model of systemic kainic acid injection that MGV-1 can prevent seizures, counteract the process of ongoing brain damage, including edema, and restore behavior defects to normal patterns. Furthermore, in the R6-2 (transgenic mouse model for Huntington disease; Strain name: B6CBA-Tg(HDexon1)62Gpb/3J) transgenic mouse model for Huntington disease, derivatives of MGV-1 can increase lifespan by >20% and reduce incidence of abnormal movements. Also in vitro, these derivatives were more effective than MGV-1.

No MeSH data available.