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

Main signaling pathways activated by cannabinoid receptors. The canonical signaling pathway initiated by the binding of a cannabinoid to CBRs involves the coupling of the receptor to Gi/0 proteins. αi subunits can inhibit the activity of adenylyl cyclase (AC) and the synthesis of cAMP. This results in a decreased activation of PKA and an increased activation of potassium channels type A, which leads to membrane hyperpolarization. α0 subunits can in turn inhibit voltage dependent Ca2+ channels contributing to the inhibition of membrane depolarization. βγ subunits interact with other intracellular pathways related to PI3K or PKB/Akt. CBRs are also coupled to neutral sphingomyelinase (EMN), an enzyme that mediates the generation of ceramide from sphingomyelin (EM) in the plasma membrane. Ceramide acts as an intracellular signaling molecule than can activate several transcription factors including ERK, JNK and p38, and is involved, among other functions, on the control of cell fate and survival. AC: adenylyl cyclase; FAN: factor associated with neutral sphingomyelinase activation; N, P/Q: voltage-dependent calcium channels type N, P/Q; PKA: protein kinase A; PKB/Akt: protein kinase B; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; FAK: focal adhesion kinase; PI3K: phosphoinositide-3 kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

brainsci-03-01043-f002: Main signaling pathways activated by cannabinoid receptors. The canonical signaling pathway initiated by the binding of a cannabinoid to CBRs involves the coupling of the receptor to Gi/0 proteins. αi subunits can inhibit the activity of adenylyl cyclase (AC) and the synthesis of cAMP. This results in a decreased activation of PKA and an increased activation of potassium channels type A, which leads to membrane hyperpolarization. α0 subunits can in turn inhibit voltage dependent Ca2+ channels contributing to the inhibition of membrane depolarization. βγ subunits interact with other intracellular pathways related to PI3K or PKB/Akt. CBRs are also coupled to neutral sphingomyelinase (EMN), an enzyme that mediates the generation of ceramide from sphingomyelin (EM) in the plasma membrane. Ceramide acts as an intracellular signaling molecule than can activate several transcription factors including ERK, JNK and p38, and is involved, among other functions, on the control of cell fate and survival. AC: adenylyl cyclase; FAN: factor associated with neutral sphingomyelinase activation; N, P/Q: voltage-dependent calcium channels type N, P/Q; PKA: protein kinase A; PKB/Akt: protein kinase B; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; FAK: focal adhesion kinase; PI3K: phosphoinositide-3 kinase.

Mentions: Two main specific receptors for endocannabinoids were cloned and characterized in the early 1990s: CB1, which in the central nervous system (CNS) is located primarily in neurons, and CB2, expressed in activated microglia and astrocytes and other immune cells that may infiltrate in the CNS under pathological conditions [51,52,53]. Both are G protein-coupled receptors, although they have been shown to associate with other intracellular signaling molecules as well. The canonical signaling pathway for CBRs involves their coupling with Gi/0 and normally results in an overall inhibitory signal. Other pathways that can be activated by the binding of cannabinoids to CBRs involve the enzymes PI3 kinase, esphingomyelinase, and phospholipase C [54] (Figure 2). The final effect of a certain cannabinergic ligand on the biology of the cell will depend on the affinity of the ligand for the receptor, the cell type, the subcellular location of the receptors and the tissue context in which the cell is placed [55]. In postsynaptic neurons, endocannabinoids are produced on demand in response to membrane depolarization upon Ca2+-dependent activation of the enzymes in charge of their biosynthesis. Endocannabinoids diffuse across the plasma membrane and reach the CB1R receptors located in the presynaptic membrane, reducing its depolarization state and inhibiting neurotransmitter release [48]. Thus, through CB1R the endocannabinoid system modulates the intensity and duration of synaptic transmission. Similarly, in immune cells (including microglia) CB2R activation has been shown to mediate an inhibitory effect on activation, cell motility and secretion of inflammatory mediators [56,57]. The intrinsic capability of the endocannabinoid system of inhibiting synaptic transmission and immune responses has arisen the interest on cannabinoids as therapeutic molecules for the prevention and treatment of CNS pathologies with an important neuroinflammatory component [58], being several manifestations of perinatal brain injury included in this group.


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

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

Main signaling pathways activated by cannabinoid receptors. The canonical signaling pathway initiated by the binding of a cannabinoid to CBRs involves the coupling of the receptor to Gi/0 proteins. αi subunits can inhibit the activity of adenylyl cyclase (AC) and the synthesis of cAMP. This results in a decreased activation of PKA and an increased activation of potassium channels type A, which leads to membrane hyperpolarization. α0 subunits can in turn inhibit voltage dependent Ca2+ channels contributing to the inhibition of membrane depolarization. βγ subunits interact with other intracellular pathways related to PI3K or PKB/Akt. CBRs are also coupled to neutral sphingomyelinase (EMN), an enzyme that mediates the generation of ceramide from sphingomyelin (EM) in the plasma membrane. Ceramide acts as an intracellular signaling molecule than can activate several transcription factors including ERK, JNK and p38, and is involved, among other functions, on the control of cell fate and survival. AC: adenylyl cyclase; FAN: factor associated with neutral sphingomyelinase activation; N, P/Q: voltage-dependent calcium channels type N, P/Q; PKA: protein kinase A; PKB/Akt: protein kinase B; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; FAK: focal adhesion kinase; PI3K: phosphoinositide-3 kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

brainsci-03-01043-f002: Main signaling pathways activated by cannabinoid receptors. The canonical signaling pathway initiated by the binding of a cannabinoid to CBRs involves the coupling of the receptor to Gi/0 proteins. αi subunits can inhibit the activity of adenylyl cyclase (AC) and the synthesis of cAMP. This results in a decreased activation of PKA and an increased activation of potassium channels type A, which leads to membrane hyperpolarization. α0 subunits can in turn inhibit voltage dependent Ca2+ channels contributing to the inhibition of membrane depolarization. βγ subunits interact with other intracellular pathways related to PI3K or PKB/Akt. CBRs are also coupled to neutral sphingomyelinase (EMN), an enzyme that mediates the generation of ceramide from sphingomyelin (EM) in the plasma membrane. Ceramide acts as an intracellular signaling molecule than can activate several transcription factors including ERK, JNK and p38, and is involved, among other functions, on the control of cell fate and survival. AC: adenylyl cyclase; FAN: factor associated with neutral sphingomyelinase activation; N, P/Q: voltage-dependent calcium channels type N, P/Q; PKA: protein kinase A; PKB/Akt: protein kinase B; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; FAK: focal adhesion kinase; PI3K: phosphoinositide-3 kinase.
Mentions: Two main specific receptors for endocannabinoids were cloned and characterized in the early 1990s: CB1, which in the central nervous system (CNS) is located primarily in neurons, and CB2, expressed in activated microglia and astrocytes and other immune cells that may infiltrate in the CNS under pathological conditions [51,52,53]. Both are G protein-coupled receptors, although they have been shown to associate with other intracellular signaling molecules as well. The canonical signaling pathway for CBRs involves their coupling with Gi/0 and normally results in an overall inhibitory signal. Other pathways that can be activated by the binding of cannabinoids to CBRs involve the enzymes PI3 kinase, esphingomyelinase, and phospholipase C [54] (Figure 2). The final effect of a certain cannabinergic ligand on the biology of the cell will depend on the affinity of the ligand for the receptor, the cell type, the subcellular location of the receptors and the tissue context in which the cell is placed [55]. In postsynaptic neurons, endocannabinoids are produced on demand in response to membrane depolarization upon Ca2+-dependent activation of the enzymes in charge of their biosynthesis. Endocannabinoids diffuse across the plasma membrane and reach the CB1R receptors located in the presynaptic membrane, reducing its depolarization state and inhibiting neurotransmitter release [48]. Thus, through CB1R the endocannabinoid system modulates the intensity and duration of synaptic transmission. Similarly, in immune cells (including microglia) CB2R activation has been shown to mediate an inhibitory effect on activation, cell motility and secretion of inflammatory mediators [56,57]. The intrinsic capability of the endocannabinoid system of inhibiting synaptic transmission and immune responses has arisen the interest on cannabinoids as therapeutic molecules for the prevention and treatment of CNS pathologies with an important neuroinflammatory component [58], being several manifestations of perinatal brain injury included in this group.

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