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

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.

Figure 1

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).

Figure 2

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 G_i/0 proteins. α_i 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.