How controversies regarding hydrogen sulfide may have occurred is discussed. Addressed are the direct and indirect pathways of hydrogen sulfide on inflammation, the effects of different concentrations of hydrogen sulfide and how the effects of hydrogen sulfide on the immune system vary with different delivery mechanisms. Furthermore, there is a discussion on what key gaps exist in current knowledge and must be addressed before hydrogen sulfide can be considered a valid pharmacological target.

Two cannabinoids receptors have been characterised in mammals; cannabinoid receptor type 1 (CBI) which is ubiquitous in the central nervous system (CNS), and cannabinoid receptor type 2 (CBII) that is expressed mainly in immune cells. Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS. This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity. This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer's disease and Parkinson's disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the anti-inflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs. Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis. In the second part of the article, we review the state of development of CBII selective drugs with an emphasis on critical aspects of CBII agonist structural activity relationship (SAR).

Neonatal cerebral ischemic injury is a common and debilitating pathology for which there is currently no known purely pharmacological treatments that are effective when delivered immediately after injury. Cyclodextrins are cyclic oligosaccharides that can remove cholesterol from cell membranes and thereby affect receptor function. Cyclodextrins have previously been shown to be neuroprotective in vitro. We showed that hydroxypropyl-β-cyclodextrin is neuroprotective in rats in vivo when delivered by intraperitoneal injection 30 min following hypoxia-ischemia, when assessed 15 days after surgery. A single dose of 1 g/kg hydroxypropyl-β-cyclodextrin reduced brain infarction size by 28.57% compared with control (P<0.001). We also report that the same compound reduces neuronal excitability in hippocampal slices and propose that hydroxypropyl-β-cyclodextrin is neuroprotective by reducing excitotoxicity in the delayed phase of brain damage.

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