Limits...
Cannabinoids: well-suited candidates for the treatment of perinatal brain injury.

Fernández-López D, Lizasoain I, Moro MA, Martínez-Orgado J - Brain Sci (2013)

Bottom Line: Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment.The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species.Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration) to neonatal brain injury has been described in independent studies.

View Article: PubMed Central - PubMed

Affiliation: Neonatal Brain Disorders Center, Department of Neurology, University of California San Francisco, San Francisco, 94158 CA, USA. David.fernandezlopez@ucsf.edu.

ABSTRACT
Perinatal brain injury can be induced by a number of different damaging events occurring during or shortly after birth, including neonatal asphyxia, neonatal hypoxia-ischemia and stroke-induced focal ischemia. Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment. In spite of the high incidence of perinatal brain injury, the number of clinical interventions available for the treatment of the affected newborn babies is extremely limited. Hence, there is a dramatic need to develop new effective therapies aimed to prevent acute brain damage and enhance the endogenous mechanisms of long-term brain repair. The endocannabinoid system is an endogenous neuromodulatory system involved in the control of multiple central and peripheral functions. An early responder to neuronal injury, the endocannabinoid system has been described as an endogenous neuroprotective system that once activated can prevent glutamate excitotoxicity, intracellular calcium accumulation, activation of cell death pathways, microglia activation, neurovascular reactivity and infiltration of circulating leukocytes across the blood-brain barrier. The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species. Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration) to neonatal brain injury has been described in independent studies. This review addresses the particular effects of several drugs that modulate the activity of the endocannabinoid system on the progression of different manifestations of perinatal brain injury during both the acute and chronic recovery phases using rodent and non-rodent animal models, and will provide a complete description of the known mechanisms that mediate such effects.

No MeSH data available.


Related in: MedlinePlus

Cannabinoids as mediators of neuronal retrograde signaling. The presence of cannabinoid receptors (CBRs) on presynaptic neurons modulates the release of neurotransmitter to the synapsis. The action potential in the presynaptic neuron causes the fusion of neurotransmitter vesicles with the plasma membrane (1). The binding of the neurotransmitter to its postsynaptic receptors induces the depolarization of the postsynaptic membrane and the accumulation of Ca2+ in the cytoplasm, inducing the activation of calcium-dependent enzymes in charge of the biosynthesis of endocannabinoids (PL, DAGL) (2). Cannabinoids produced de novo diffuse through the postsynaptic membrane, binding to the presynaptic CBRs (3). The activation of CBRs promotes the hyperpolarization of the presynaptic membrane (4) and modulates the release of neurotransmitter, regulating synaptic transmission. Endocannabinoids are internalized by a selective transporter (AMT) and degraded by specific enzymes (FAAH, MAGL) (5).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061885&req=5

brainsci-03-01043-f001: Cannabinoids as mediators of neuronal retrograde signaling. The presence of cannabinoid receptors (CBRs) on presynaptic neurons modulates the release of neurotransmitter to the synapsis. The action potential in the presynaptic neuron causes the fusion of neurotransmitter vesicles with the plasma membrane (1). The binding of the neurotransmitter to its postsynaptic receptors induces the depolarization of the postsynaptic membrane and the accumulation of Ca2+ in the cytoplasm, inducing the activation of calcium-dependent enzymes in charge of the biosynthesis of endocannabinoids (PL, DAGL) (2). Cannabinoids produced de novo diffuse through the postsynaptic membrane, binding to the presynaptic CBRs (3). The activation of CBRs promotes the hyperpolarization of the presynaptic membrane (4) and modulates the release of neurotransmitter, regulating synaptic transmission. Endocannabinoids are internalized by a selective transporter (AMT) and degraded by specific enzymes (FAAH, MAGL) (5).

Mentions: The endocannabinoid system is a neuromodulatory system comprised by endogenous ligands or endocannabinoids (being N-arachidonoylethanolamine, anandamide or AEA, and 2-arachidonoylglycerol, 2-AG, the most abundant), specific and non-specific receptors for both endogenous and exogenous ligands and enzymes that degrade endocannabinoids in the cytosol [44]. It has been proposed that the uptake of endocannabinoids from the extracellular space occurs by facilitated diffusion mediated by a selective transporter, although experimental evidences for the existence of such molecule remain controversial [45]. The specific cannabinoid receptors (CBRs) are expressed in numerous cell types in the body and modulate a plethora of biological functions. In the central nervous system (CNS) the endocannabinoid system participates, among other functions, in the control of motor coordination, memory and learning, body temperature, appetite and pain [46,47]. Most neural functions controlled by endocannabinoid signaling depend on the neuronal cannabinoid receptor type 1 (CBR1). This receptor is the primary mediator of the inhibition of neurotransmission by retrograde signaling mediated by endocannabinoids [48], a neuromodulatory mechanism of neuronal depolarization and neurotransmitter release that is described in more detail in Figure 1.


Cannabinoids: well-suited candidates for the treatment of perinatal brain injury.

Fernández-López D, Lizasoain I, Moro MA, Martínez-Orgado J - Brain Sci (2013)

Cannabinoids as mediators of neuronal retrograde signaling. The presence of cannabinoid receptors (CBRs) on presynaptic neurons modulates the release of neurotransmitter to the synapsis. The action potential in the presynaptic neuron causes the fusion of neurotransmitter vesicles with the plasma membrane (1). The binding of the neurotransmitter to its postsynaptic receptors induces the depolarization of the postsynaptic membrane and the accumulation of Ca2+ in the cytoplasm, inducing the activation of calcium-dependent enzymes in charge of the biosynthesis of endocannabinoids (PL, DAGL) (2). Cannabinoids produced de novo diffuse through the postsynaptic membrane, binding to the presynaptic CBRs (3). The activation of CBRs promotes the hyperpolarization of the presynaptic membrane (4) and modulates the release of neurotransmitter, regulating synaptic transmission. Endocannabinoids are internalized by a selective transporter (AMT) and degraded by specific enzymes (FAAH, MAGL) (5).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061885&req=5

brainsci-03-01043-f001: Cannabinoids as mediators of neuronal retrograde signaling. The presence of cannabinoid receptors (CBRs) on presynaptic neurons modulates the release of neurotransmitter to the synapsis. The action potential in the presynaptic neuron causes the fusion of neurotransmitter vesicles with the plasma membrane (1). The binding of the neurotransmitter to its postsynaptic receptors induces the depolarization of the postsynaptic membrane and the accumulation of Ca2+ in the cytoplasm, inducing the activation of calcium-dependent enzymes in charge of the biosynthesis of endocannabinoids (PL, DAGL) (2). Cannabinoids produced de novo diffuse through the postsynaptic membrane, binding to the presynaptic CBRs (3). The activation of CBRs promotes the hyperpolarization of the presynaptic membrane (4) and modulates the release of neurotransmitter, regulating synaptic transmission. Endocannabinoids are internalized by a selective transporter (AMT) and degraded by specific enzymes (FAAH, MAGL) (5).
Mentions: The endocannabinoid system is a neuromodulatory system comprised by endogenous ligands or endocannabinoids (being N-arachidonoylethanolamine, anandamide or AEA, and 2-arachidonoylglycerol, 2-AG, the most abundant), specific and non-specific receptors for both endogenous and exogenous ligands and enzymes that degrade endocannabinoids in the cytosol [44]. It has been proposed that the uptake of endocannabinoids from the extracellular space occurs by facilitated diffusion mediated by a selective transporter, although experimental evidences for the existence of such molecule remain controversial [45]. The specific cannabinoid receptors (CBRs) are expressed in numerous cell types in the body and modulate a plethora of biological functions. In the central nervous system (CNS) the endocannabinoid system participates, among other functions, in the control of motor coordination, memory and learning, body temperature, appetite and pain [46,47]. Most neural functions controlled by endocannabinoid signaling depend on the neuronal cannabinoid receptor type 1 (CBR1). This receptor is the primary mediator of the inhibition of neurotransmission by retrograde signaling mediated by endocannabinoids [48], a neuromodulatory mechanism of neuronal depolarization and neurotransmitter release that is described in more detail in Figure 1.

Bottom Line: Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment.The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species.Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration) to neonatal brain injury has been described in independent studies.

View Article: PubMed Central - PubMed

Affiliation: Neonatal Brain Disorders Center, Department of Neurology, University of California San Francisco, San Francisco, 94158 CA, USA. David.fernandezlopez@ucsf.edu.

ABSTRACT
Perinatal brain injury can be induced by a number of different damaging events occurring during or shortly after birth, including neonatal asphyxia, neonatal hypoxia-ischemia and stroke-induced focal ischemia. Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment. In spite of the high incidence of perinatal brain injury, the number of clinical interventions available for the treatment of the affected newborn babies is extremely limited. Hence, there is a dramatic need to develop new effective therapies aimed to prevent acute brain damage and enhance the endogenous mechanisms of long-term brain repair. The endocannabinoid system is an endogenous neuromodulatory system involved in the control of multiple central and peripheral functions. An early responder to neuronal injury, the endocannabinoid system has been described as an endogenous neuroprotective system that once activated can prevent glutamate excitotoxicity, intracellular calcium accumulation, activation of cell death pathways, microglia activation, neurovascular reactivity and infiltration of circulating leukocytes across the blood-brain barrier. The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species. Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration) to neonatal brain injury has been described in independent studies. This review addresses the particular effects of several drugs that modulate the activity of the endocannabinoid system on the progression of different manifestations of perinatal brain injury during both the acute and chronic recovery phases using rodent and non-rodent animal models, and will provide a complete description of the known mechanisms that mediate such effects.

No MeSH data available.


Related in: MedlinePlus