*Review* **The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic–Ischemic Brain Injury**

**Andrea Duranti 1,\*, Gorane Beldarrain 2, Antonia Álvarez 2, Matilde Sbriscia 1, Silvia Carloni 1 Walter Balduini 1 and Daniel Alonso-Alconada 2,\***


**Abstract:** The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This neuromodulatory system is also involved in the response to endogenous and environmental insults, being of special relevance in the prevention and/or treatment of vascular disorders, such as stroke and neuroprotection after neonatal brain injury. Perinatal hypoxia–ischemia leading to neonatal encephalopathy is a devastating condition with no therapeutic approach apart from moderate hypothermia, which is effective only in some cases. This overview, therefore, gives a current description of the main components of the EC system (including cannabinoid receptors, ligands, and related enzymes), to later analyze the EC system as a target for neonatal neuroprotection with a special focus on its neurogenic potential after hypoxic–ischemic brain injury.

**Keywords:** endocannabinoid system; cannabinoid receptors; FAAH inhibitors; MGL inhibitors; neonatal brain injury; hypoxia–ischemia; neuroprotection; neurogenesis

#### **1. The Endocannabinoid System**

The endocannabinoid (EC) system is a cell-signaling system consisting mainly of at least two cannabinoid (CB) receptors, namely CB1 and CB2, their endogenous ligands, and the enzymes responsible for the synthesis, transport, and degradation of endocannabinoids (ECs) [1]. Changes in the expression or activity of CB receptors, ligands, or enzymes are implicated in many pathological conditions [2]. Neurological disorders such as anxiety, depression, schizophrenia, neurodegenerative (e.g., Parkinson's and Huntington's disease), and stroke-related disorders, together with osteoporosis, multiple sclerosis, neuropathic pain, cancer, glaucoma, hypertension, and obesity/metabolic syndrome are just the major diseases associated with perturbations of the EC system [3]. Recently, it has been hypothesized that CB2 receptor activation may be also useful to reduce the inflammatory response induced by SARS-CoV-2 infection, due to its capacity to ameliorate the production of cytokines responsible for the pathological phenomenon [4].

However, changes in EC tone are sometimes transient and likely part of the organism's compensatory response mainly aimed at reducing symptoms or slowing the progression of pathological conditions. In the nervous system, the activity of the EC system also appears related to neuroprotection, because of its ability to modulate the intensity and extent of a series of dangerous biological events involved in the neurodegenerative process. These include modulation of glutamate excitotoxicity [5] and oxidative stress [6], and a reduction in the inflammatory response [7]. This scenario led to considering the EC system

**Citation:** Duranti, A.; Beldarrain, G.;Álvarez, A.; Sbriscia, M.; Carloni, S.; Balduini, W.; Alonso-Alconada, D. The Endocannabinoid System as a Target for Neuroprotection/ Neuroregeneration in Perinatal Hypoxic–Ischemic Brain Injury. *Biomedicines* **2023**, *11*, 28. https://doi.org/10.3390/ biomedicines11010028

Academic Editor: Wesley M. Raup-Konsavage

Received: 18 November 2022 Accepted: 19 December 2022 Published: 22 December 2022

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

as a potential target for developing new neuroprotective therapies [3]. However, it is not always clear whether an increased activity of the EC system can be consequent to a higher biosynthetic activity or a reduction in the metabolic degradation of the endogenous ligands. Therefore, a better understanding of the role and mechanisms underlying EC tone alterations during the neurodegenerative process represents key factors for developing new therapeutic agents acting through this important modulatory system.

Overall, despite the vast amount of knowledge acquired over time, the exploration of the EC system still represents a stimulating goal. Indeed, the complexity of its structures, the species variability of its characteristics, and the overlapping of pharmacological targets, still leave open many questions and scientific opportunities. This review aims to highlight the potential role of the EC system in the neurodegenerative and neuro-reparative processes resulting from hypoxic–ischemic insults occurring during brain development. A summary of CB receptors, ligands, and related enzymes is also reported.
